This invention relates to novel lactams having drug and bio-affecting properties, their pharmaceutical compositions and methods of use. These novel compounds inhibit the processing of amyloid precursor protein and, more specifically, inhibit the production of Axcex2-peptide, thereby acting to prevent the formation of neurological deposits of amyloid protein. More particularly, the present invention relates to the treatment of neurological disorders related to xcex2-amyloid production such as Alzheimer""s disease and Down""s Syndrome.
Alzheimer""s disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, temporal and local orientation, cognition, reasoning, judgment and emotional stability. AD is a common cause of progressive dementia in humans and is one of the major causes of death in the United States. AD has been observed in all races and ethnic groups worldwide, and is a major present and future health problem. No treatment that effectively prevents AD or reverses the clinical symptoms and underlying pathophysiology is currently available (for review, Dennis J. Selkoe; Cell Biology of the amyloid (beta)-protein precursor and the mechanism of Alzheimer""s disease, Annu Rev Cell Biol, 1994, 10: 373-403).
Histopathological examination of brain tissue derived upon autopsy or from neurosurgical specimens in effected individuals revealed the occurrence of amyloid plaques and neurofibrillar tangles in the cerebral cortex of such patients. Similar alterations were observed in patients with Trisomy 21 (Down""s syndrome), and hereditary cerebral hemorrhage with amyloidosis of the Dutch-type. Neurofibrillar tangles are nonmembrane-bound bundles of abnormal proteinaceous filaments and biochemical and immunochemical studies led to the conclusion that their principle protein subunit is an altered phosphorylated form of the tau protein (reviewed in Selkoe, 1994).
Biochemical and immunological studies revealed that the dominant proteinaceous component of the amyloid plaque is an approximately 4.2 kilodalton (kD) protein of about 39 to 43 amino acids. This protein was designated Axcex2, xcex2-amyloid peptide, and sometimes xcex2/A4; referred to herein as Axcex2. In addition to deposition of Axcex2 in amyloid plaques, Axcex2 is also found in the walls of meningeal and parenchymal arterioles, small arteries, capillaries, and sometimes, venules. Axcex2 was first purified, and a partial amino acid reported, in 1984 (Glenner and Wong, Biochem. Biophys. Res. Commun. 120: 885-890). The isolation and sequence data for the first 28 amino acids are described in U.S. Pat. No 4,666,829.
Compelling evidence accumulated during the last decade revealed that Axcex2 is an internal polypeptide derived from a type 1 integral membrane protein, termed b amyloid precursor protein (APP). xcex2 APP is normally produced by many cells both in vivo and in cultured cells, derived from various animals and humans. AP is derived from cleavage of xcex2 APP by as yet unknown enzyme (protease) system(s), collectively termed secretases.
The existence of at least four proteolytic activities has been postulated. They include xcex2 secretase(s), generating the N-terminus of Axcex2, a secretase(s) cleaving around the 16/17 peptide bond in Axcex2, and y secretases, generating C-terminal Axcex2 fragments ending at position 38, 39, 40, 42, and 43 or generating C-terminal extended precursors which are subsequently truncated to the above polypeptides.
Several lines of evidence suggest that abnormal accumulation of Axcex2 plays a key role in the pathogenesis of AD. Firstly, Axcex2 is the major protein found in amyloid plaques. Secondly, Axcex2 is neurotoxic and may be causally related to neuronal death observed in AD patients. Thirdly, missense DNA mutations at position 717 in the 770 isoform of xcex2 APP can be found in effected members but not unaffected members of several families with a genetically determined (familiar) form of AD. In addition, several other b APP mutations have been described in familiar forms of AD. Fourthly, similar neuropathological changes have been observed in transgenic animals overexpressing mutant forms of human xcex2 APP. Fifthly, individuals with Down""s syndrome have an increased gene dosage of b APP and develop early-onset AD. Taken together, these observations strongly suggest that Axcex2 depositions may be causally related to the AD.
It is hypothesized that inhibiting the production of Axcex2 will prevent and reduce neurological degeneration, by controlling the formation of amyloid plaques, reducing neurotoxicity and, generally, mediating the pathology associated with Axcex2 production. One method of treatment methods would therefore be based on drugs that inhibit the formation of Axcex2 in vivo.
Methods of treatment could target the formation of Axcex2 through the enzymes involved in the proteolytic processing of xcex2 amyloid precursor protein. Compounds that inhibit xcex2 or xcex3 secretase activity, either directly or indirectly, could control the production of Axcex2. Advantageously, compounds that specifically target xcex3 secretases, could control the production of Axcex2. Such inhibition of xcex2 or xcex3 secretases could thereby reduce production of Axcex2, which, thereby, could reduce or prevent the neurological disorders associated with Axcex2 protein.
PCT publication number WO 96/29313 discloses the general formula: 
covering metalloprotease inhibiting compounds useful for the treatment of diseases associated with excess and/or unwanted matrix metalloprotease activity, particularly collagenase and or stromelysin activity.
Compounds of general formula: 
are disclosed in PCT publication number WO 95/22966 relating to matrix metalloprotease inhibitors. The compounds of the invention are useful for the treatment of conditions associated with the destruction of cartilage, including corneal ulceration, osteoporosis, periodontitis and cancer.
European Patent Application number EP 0652009A1 relates to the general formula: 
and discloses compounds that are protease inhibitors that inhibit AD production.
U.S. Pat. No. 5703129 discloses the general formula: 
which covers 5-amino-6-cyclohexyl-4-hydroxy-hexanamide derivatives that inhibit AD production and are useful in the treatment of Alzheimer""s disease.
None of the above references teaches or suggests the compounds of the present invention which are described in detail below.
One object of the present invention is to provide novel compounds which are useful as inhibitors of the production of Axcex2 protein or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating degenerative neurological disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of Formula (I): 
or pharmaceutically acceptable salt or prodrug forms thereof, wherein R3, R3a, R5, R5a, R6, Q, B, W, X, Y, and Z are defined below, are effective inhibitors of the production of Axcex2.
Thus, in a first embodiment, the present invention provides a novel compound of Formula (I): 
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
Q is xe2x80x94OR1 or xe2x80x94NR1R2;
ring B is selected from the group consisting of:
a carbocyclic group of 3 to 8 carbon atoms wherein the carbocyclic group is saturated, partially saturated or unsaturated;
a heterocycle of 3 to 8 atoms containing a heteroatom selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, and xe2x80x94N(R10)xe2x80x94;
a bicyclic ring system selected from the group consisting of: 
a tricyclic ring system selected from the group consisting of: 
a tetracyclic ring system selected from the group consisting of: 
s is 0, 1, 2, 3, 4, 5, or 6;
R1, at each occurrence, is independently selected from: H;
C1-C6 alkyl substituted with 0-3 R1a;
C2-C6 alkenyl substituted with 0-3 R1a;
C3-C10 carbocycle substituted with 0-3 R1b;
C6-C10 aryl substituted with 0-3 R1b; and
5 to 10 membered heterocycle substituted with 0-3 R1b;
R1a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, CF3;
C3-C10 carbocycle substituted with 0-3 R1b;
C6-C10 aryl substituted with 0-3 R1b; and
5 to 6 membered heterocycle substituted with 0-3 R1b;
R1b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
R2 is independently selected from H, NH2, OH, C1-C6 alkyl, C1-C6 alkoxy, phenoxy, benzyloxy, C3-C10 carbocycle, C6-C10 aryl and 5 to 10 membered heterocycle;
R3 is xe2x80x94(CR7R7a)nxe2x80x94R4,
xe2x80x94(CR7R7a)-S -(CR7R7a)mxe2x80x94R4,
xe2x80x94(CR7R7a)nxe2x80x94O-(CR7R7a)mxe2x80x94R4,
xe2x80x94(CR7R7a)nxe2x80x94N(R7b)xe2x80x94(CR7R7a)mxe2x80x94R4,
xe2x80x94(CR7R7a)nxe2x80x94S(xe2x95x90O)xe2x80x94(CR7R7a)mxe2x80x94R4,
xe2x80x94(CR7R7a)nxe2x80x94S(xe2x95x90O)2xe2x80x94(CR7R7a)mxe2x80x94R4,
xe2x80x94(CR7R7a)nxe2x80x94C(xe2x95x90O)xe2x80x94(CR7R7a)mxe2x80x94R4,
xe2x80x94(CR7R7a)nxe2x80x94N(R7b)C(xe2x95x90O)xe2x80x94(CR7R7a)mxe2x80x94R4,
xe2x80x94(CR7R7a)nxe2x80x94C(xe2x95x90O)N(R7b)xe2x80x94(CR7R7a)mxe2x80x94R4 
xe2x80x94(CR7R7a)nxe2x80x94N(R7b)S(xe2x95x90O)2xe2x80x94(CR7R7a)mxe2x80x94R4, or
xe2x80x94(CR7R7a)nxe2x80x94S(xe2x95x90O)2N(R7b)xe2x80x94(CR7R7a)mxe2x80x94R4;
n is 0, 1, 2,or 3;
m is 0, 1, 2, or 3;
R3a is H, OH, C1-C4 alkyl, C1-C4 alkoxy, or C2-C4 alkenyloxy;
alternatively, R3 and R3a may be combined to form a 3-7 membered carbocyclic moiety;
wherein said 3-7 membered carbocyclic moiety is saturated or partially unsaturated;
wherein said 3-7 membered carbocyclic moiety may optionally contain a heteroatom selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94Nxe2x95x90, xe2x80x94NHxe2x80x94, and xe2x80x94N(R20)xe2x80x94, and
wherein said 3-7 membered carbocyclic moiety is substituted with 0-4 R4;
additionally, two R4 substituents on adjacent atoms may be combined to form a benzo fused radical; wherein said benzo fused radical is substituted with 0-4 R23;
additionally, two R4 substituents on adjacent atoms may be combined to form a 5 to 6 membered heteroaryl fused radical, wherein said 5 to 6 membered heteroaryl fused radical comprises 1 or 2 heteroatoms selected from N, O, and S; wherein said 5 to 6 membered heteroaryl fused radical is substituted with 0-3 R23; additionally, two R4 substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle substituted with 0-3 R23;
R4 is H, OH, OR14a,
C1-C6 alkyl substituted with 0-3 R4a,
C2-C6 alkenyl substituted with 0-3 R4a,
C2-C6 alkynyl substituted with 0-3 R4a,
C3-C10 carbocycle substituted with 0-3 R4b, C6-C10 aryl substituted with 0-3 R4b, or
5 to 10 membered heterocycle substituted with 0-3 R4b;
R4a, at each occurrence, is independently selected from is H, F, Cl, Br, I, CF3,
C3-C10 carbocycle substituted with 0-3 R4b,
C6-C10 aryl substituted with 0-3 R4b, or
5 to 10 membered heterocycle substituted with 0-3 R4b;
R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 halothioalkoxy;
R5 is H, OR14;
C1-C6 alkyl substituted with 0-3 R5b;
C1-C6 alkoxy substituted with 0-3 R5b;
C2-C6 alkenyl substituted with 0-3 R5b;
C2-C6 alkynyl substituted with 0-3 R5b;
C3-C10 carbocycle substituted with 0-3 R5c;
C6-C10 aryl substituted with 0-3 R5c; or
5 to 10 membered heterocycle substituted with 0-3R5c;
R5a is H, OH, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, or C2-C4 alkenyloxy;
R5b, at each occurrence, is independently selected from:
H, C1-C6 alkyl, CF3, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16;
C3-C10 carbocycle substituted with 0-3 R5c;
C6-C10 aryl substituted with 0-3 R5c; or
5 to 10 membered heterocycle substituted with 0-3 R5c;
R5c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 halothioalkoxy;
alternatively, R5 and R5a may be combined to form a 3-7 membered carbocyclic ring substituted with 0-3 R5c; optionally the carbocyclic ring formed by combining R5 and R5a may be benzo fused, wherein the benzo fused ring may be substituted with 0-3 R5c;
R6 is H;
C1-C6 alkyl substituted with 0-3 R6a;
C3-C10 carbocycle substituted with 0-3 R6b; or
C6-C10 aryl substituted with 0-3R6b;
R6a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, phenyl or CF3;
R6b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
R7, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, and C1-C4 alkyl;
R7a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, aryl and C1-C4 alkyl;
R7b is independently selected from H and C1-C4 alkyl;
W is xe2x80x94(CR8R8a)pxe2x80x94;
p is 0, 1, 2, 3, or 4;
R8 and R8a, at each occurrence, are independently selected from H, F, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl and C3-C8 cycloalkyl;
X is a bond;
C6-C10 aryl substituted with 0-3 RXb;
C3-C1O carbocycle substituted with 0-3 RXb; or
5 to 10 membered heterocycle substituted with 0-2 RXb;
RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 halothioalkoxy;
Y is a bond or xe2x80x94(CR9R9a)txe2x80x94Vxe2x80x94(CR9R9a)uxe2x80x94;
t is 0, 1, 2, or 3;
u is 0, 1, 2, or 3;
R9 and R9a, at each occurrence, are independently selected from H, F, C1-C6 alkyl or C3-C8 cycloalkyl;
V is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94N(R19)xe2x80x94, xe2x80x94C(xe2x95x90O)NR19bxe2x80x94, xe2x80x94NR19bC(xe2x95x90O)xe2x80x94, xe2x80x94NR19bS(xe2x95x90O)2xe2x80x94, xe2x80x94S(xe2x95x90O)2NR19bxe2x80x94, xe2x80x94NR19bS(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)NR19bxe2x80x94xe2x80x94C(xe2x95x90O)Oxe2x80x94, or xe2x80x94OC(xe2x95x90O)xe2x80x94;
Z is H;
C1-C8 alkyl substituted with 0-3 R12a;
C2-C4 alkenyl substituted with 0-3 R12a;
C2-C4 alkynyl substituted with 0-3 R12a;
C6-C10 aryl substituted with 0-4 R12a;
C3-C10 carbocycle substituted with 0-4 R12a; or
5 to 10 membered heterocycle substituted with 0-3 R12a;
R12a at each occurrence, is independently selected from
H, OH, Cl, F, Br, I, CN, NO2, NR15R16, xe2x80x94C(xe2x95x90O)NR15R16, CF3, acetyl,
SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, C1-C4 haloalkyl-Sxe2x80x94,
C1-C3 alkyl substituted with 0-1 R12c;
C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-S-;
R12c, at each occurrence, is independently selected from
C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R10 is H, C(xe2x95x90O)R17, C(xe2x95x90O)OR17, C(xe2x95x90O)NR18R19, S(xe2x95x90O)2NR18R19, S(xe2x95x90O)2R17;
C1-C6 alkyl substituted with 0-2 R10a;
C6-C10 aryl substituted with 04 R10b;
C3-C10 carbocycle substituted with 0-3 R10b; or
5 to 10 membered heterocycle optionally substituted with 0-3 R10b;
R10a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, CF3, or aryl substituted with 0-4 R10b;
R10b, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 halothioalkoxy;
alternatively, R10 may be xe2x80x94Wxe2x80x94Xxe2x80x94Yxe2x80x94Z;
R11, at each occurrence, is independently selected from H, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR18R19, C(xe2x95x90O)R17, C(xe2x95x90O)OR17, C(xe2x95x90O)NR18R19, S(xe2x95x90O)2NR18R19, CF3;
C1-C6 alkyl substituted with 0-1 R11a;
C6-C10 aryl substituted with 0-3 R11b;
C3-C10 carbocycle substituted with 0-3 R11b; or
5 to 10 membered heterocycle substituted with 0-3 R11b;
alternatively, two R11 substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle or a benzo fused radical; wherein said benzo fused radical is substituted with 0-4 R13;
R11a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 halothioalkoxy;
R13, at each occurrence, is independently selected from
H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
R14, at each occurrence, is independently selected from H, phenyl, benzyl, C1-C6 alkyl, or C2-C6 alkoxyalkyl;
R14a is H, phenyl, benzyl, or C1-C4 alkyl;
R15, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C6 alkyl);
R16, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C6 alkyl);
R17 is H, aryl, aryl-CH2xe2x80x94, C1-C6 alkyl, or C2-C6 alkoxyalkyl;
R18, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C6 alkyl); and
R19, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, phenyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C6 alkyl); and
R19b is H, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, benzyl or phenethyl; additionally, R18 and R19, when substituents on the same atom, may be combined to form a 3 to 7 membered heterocyclic ring;
R20 is H, C(xe2x95x90O)R17, C(xe2x95x90O)OR17, C(xe2x95x90O)NR18R19,
S(xe2x95x90O)2NR18R19, S(xe2x95x90O)2R17;
C1-C6 alkyl optionally substituted with 0-3 R20a; or
C6-C10 aryl substituted with 0-4 R20b;
R20a, at each occurrence, is independently selected from H, C1-C4 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, CF3, or aryl substituted with 0-4 R20b;
R20b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R23, at each occurrence, is independently selected from
H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16 and CF3.
[2] In a preferred embodiment the present invention provides a compound of Formula (Ia): 
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
ring B is selected from the group consisting of:
a carbocyclic group of 5 to 7 carbon atoms wherein the carbocyclic group is saturated, partially saturated or unsaturated;
a heterocycle of 5 to 7 atoms containing a heteroatom selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, and xe2x80x94N(R10)xe2x80x94;
a bicyclic ring system selected from the group consisting of: 
a tricyclic ring system selected from the group consisting of: 
a tetracyclic ring system selected from the group consisting of: 
s is, 1, 2, 3,or 4;
R3 is xe2x80x94(CR7R7a)nxe2x80x94R4,
xe2x80x94(CR7R7a)nxe2x80x94Sxe2x80x94R4,
xe2x80x94(CR7R7a)nxe2x80x94OR4,
xe2x80x94(CR7R7a)nxe2x80x94N(R7b)nxe2x80x94R4,
xe2x80x94(CR7R7a)nxe2x80x94S(xe2x95x90O)xe2x80x94R4,
xe2x80x94(CR7R7a)nxe2x80x94S(xe2x95x90O)2xe2x80x94R4, or
xe2x80x94(CR7R7a)nxe2x80x94C(xe2x95x90O)xe2x80x94R4;
n is 0, 1, or 2;
R3a is H, OH, C1-C4 alkyl, C1-C4 alkoxy, or C2-C4 alkenyloxy;
alternatively, R3 and R3a may be combined to form a 3-7 membered carbocyclic moiety;
wherein said 3-7 membered carbocyclic moiety is saturated or partially unsaturated;
wherein said 3-7 membered carbocyclic moiety may optionally contain a heteroatom selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94Nxe2x95x90, xe2x80x94NHxe2x80x94, and xe2x80x94N(R20)xe2x80x94, and
wherein said 3-7 membered carbocyclic moiety is substituted with 0-4 R4;
additionally, two R4 substituents on adjacent atoms may be combined to form a benzo fused radical; wherein said benzo fused radical is substituted with 0-4 R23;
additionally, two R4 substituents on adjacent atoms may be combined to form a 5 to 6 membered heteroaryl fused radical, wherein said 5 to 6 membered heteroaryl fused radical comprises 1 or 2 heteroatoms selected from N, O, and S; wherein said 5 to 6 membered heteroaryl fused radical is substituted with 0-3 R23;
additionally, two R4 substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle substituted with 0-3 R23;
R4 is H, OH, OR14a,
C1-C6 alkyl substituted with 0-3 R4a,
C2-C6 alkenyl substituted with 0-3 R4a,
C2-C6 alkynyl substituted with 0-3 R4a,
C3-C10 carbocycle substituted with 0-3 R4b,
C6-C10 aryl substituted with 0-3 R4b, or
5 to 10 membered heterocycle substituted with 0-3 R4b;
R4a, at each occurrence, is independently selected from is H, F, Cl, Br, I, CF3,
C3-C10 carbocycle substituted with 0-3 R4b,
C6-C10 aryl substituted with 0-3 R4b, or 5 to 10 membered heterocycle substituted with 0-3 R4b;
R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 halothioalkoxy;
R5 is H;
C1-C6 alkyl substituted with 0-3 R5b;
C2-C6 alkenyl substituted with 0-3 R5b;
C2-C6 alkynyl substituted with 0-3 R5b;
C3-C10 carbocycle substituted with 0-3 R5c; or C6-C10 aryl substituted with 0-3 R5c;
R5a is H, C1-C4 alkyl, or C2-C4 alkenyl;
R5b, at each occurrence, is independently selected from:
H, C1-C6 alkyl, CF3, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16;
C3-C10 carbocycle substituted with 0-3 R5c;
C6-C10 aryl substituted with 0-3 R5c; or
5 to 10 membered heterocycle substituted with 0-3 R5c;
R5c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 halothioalkoxy;
alternatively, R5 and R5a may be combined to form a 3-7 membered carbocyclic ring substituted with 0-3 R5c; optionally the carbocyclic ring formed by combining R5 and R5a may be benzo fused, wherein the benzo fused ring may be substituted with 0-3 R5c;
R6 is H;
C1-C6 alkyl substituted with 0-3 R6a;
C3-C10 carbocycle substituted with 0-3 R6b; or
C6-C10 aryl substituted with 0-3R6b;
R6a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, phenyl or CF3;
R6b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
R7, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, and C1-C4 alkyl;
R7a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, aryl and C1-C4 alkyl;
R7b is independently selected from H and C1-C4 alkyl;
W is xe2x80x94(CR8R8a)pxe2x80x94;
p is 0, 1, 2, or 3;
R8 and R8a, at each occurrence, are independently selected from H, F, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl and C3-C8 cycloalkyl;
X is a bond;
C6-C10 aryl substituted with 0-3 RXb;
C3-C10 carbocycle substituted with 0-3 RXb; or
5 to 10 membered heterocycle substituted with 0-2 RXb;
RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 halothioalkoxy;
Y is a bond or xe2x80x94(CR9R9a)txe2x80x94Vxe2x80x94(CR9R9a)uxe2x80x94;
t is 0, 1, 2, or 3;
u is 0, 1, 2, or 3;
R9 and R9a, at each occurrence, are independently selected from H, F, C1-C6 alkyl or C3-C8 cycloalkyl;
V is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94N(R19)xe2x80x94, xe2x80x94C(xe2x95x90O)NR19bxe2x80x94, xe2x80x94NR19bC(xe2x95x90O)xe2x80x94, xe2x80x94NR19bS(xe2x95x90O)2xe2x80x94, xe2x80x94S(xe2x95x90O)2NR19bxe2x80x94, xe2x80x94NR19bS(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)NR19bxe2x80x94, xe2x80x94C(xe2x95x90O)Oxe2x80x94, or xe2x80x94OC(xe2x95x90O)xe2x80x94;
Z is H;
C1-C8 alkyl substituted with 0-3 R12a;
C2-C4 alkenyl substituted with 0-3 Rl2a;
C2-C4 alkynyl substituted with 0-3 R12a;
C6-C10 aryl substituted with 0-4 R12a;
C3-C10 carbocycle substituted with 0-4 R12a; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12a; or
R12a, at each occurrence, is independently selected from
H, OH, Cl, F, Br, I, CN, NO2, NR15R16, xe2x80x94C(xe2x95x90O)NR15R16, CF3, acetyl, SCH3,
S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, C1-C4 haloalkyl-Sxe2x80x94,
C1-C3 alkyl substituted with 0-1 R12c;
C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 halothioalkoxy;
R12c, at each occurrence, is independently selected from
C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R10 is H, C(xe2x95x90O)R17, C(xe2x95x90O)OR17, C(xe2x95x90O)NR18R19, S(xe2x95x90O)2NR18R19, S(xe2x95x90O)2R17;
C1-C6 alkyl substituted with 0-2 R10a;
C6-C10 aryl substituted with 0-4 R10b;
C3-C10 carbocycle substituted with 0-3 R10b; or
5 to 10 membered heterocycle optionally substituted with 0-3 R10b;
R10a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, CF3, or aryl substituted with 0-4 R10b;
R10b, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 halothioalkoxy;
alternatively, R10 may be xe2x80x94Wxe2x80x94Xxe2x80x94Yxe2x80x94Z;
R11, at each occurrence, is independently selected from H,
C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR18R19, C(xe2x95x90O)Rl7, C(xe2x95x90O)OR17, C(xe2x95x90O)NR18R19, S(xe2x95x90O)2NR18R19, CF3;
C1-C6 alkyl substituted with 0-1 R11a;
C6-C10 aryl substituted with 0-3 R11b;
C3-C10 carbocycle substituted with 0-3 R11b; or
5 to 10 membered heterocycle substituted with 0-3 R11b; alternatively, two R11 substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle or a benzo fused radical; wherein said benzo fused radical is substituted with 0-4 R13;
R11a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 halothioalkoxy;
R13, at each occurrence, is independently selected from
H, OH, Cl-C6 alkyl, Cl-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15Rl6, and CF3;
R14, at each occurrence, is independently selected from H, phenyl, benzyl, C1-C6 alkyl, or C2-C6 alkoxyalkyl;
R14a is H, phenyl, benzyl, or C1-C4 alkyl;
R15, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C6 alkyl);
R16, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C6 alkyl);
R17 is H, aryl, aryl-CH2xe2x80x94, C1-C6 alkyl, or C2-C6 alkoxyalkyl;
R18, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C6 alkyl); and
R19, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, phenyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C6 alkyl); and
R19b is H, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, benzyl or phenethyl;
additionally, R18 and R19, when substituents on the same atom, may be combined to form a 3 to 7 membered heterocyclic ring;
R20 is H, C(xe2x95x90O)R17, C(xe2x95x90O)OR17, C(xe2x95x90O)NR18R19,
S(xe2x95x90O)2NR18R19, S(xe2x95x90O)2R17;
C1-C6 alkyl optionally substituted with 0-3 R20a; or
C6-C10 aryl substituted with 0-4 R20b;
R20a, at each occurrence, is independently selected from H, C1-C4 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, CF3, or aryl substituted with 0-4 R20b;
R20b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R23, at each occurrence, is independently selected from
H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3.
[3] In another preferred embodiment the present invention provides a compound of Formula (Ia): 
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
ring B is selected from the group consisting of:
a carbocyclic group of 5, 6, or 7 carbon atoms selected from -cyclopentylene-, -cyclohexylene-, -cycloheptylene-, -cyclopentenylene-, -cyclohexenylene-, and -phenylene-;
a heterocycle of 5, 6, or 7 atoms selected from -pyrrolidinylene-, -piperidinylene-, -homopiperidinylene-, and -thiophenylene-;
a bicyclic ring system selected from the group consisting of: 
a tricyclic ring system selected from the group consisting of: 
a tetracyclic ring system selected from the group consisting of: 
s is 0, 1, 2, 3, or 4;
R3 is xe2x80x94(CH2)nxe2x80x94R4;
n is 0, 1,or2;
R3a is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, or butoxy;
alternatively, R3 and R3a may be combined to form a 3-7 membered carbocyclic moiety;
wherein said 3-7 membered carbocyclic moiety is saturated or partially unsaturated;
wherein said 3-7 membered carbocyclic moiety is substituted with 0-2 R4;
R4isH,OH,
C1-C4 alkyl substituted with 0-2 R4a,
C2-C4 alkenyl substituted with 0-2 R4a,
C2-C4 alkynyl substituted with 0-1 R4a,
C3-C6 cycloklyl substituted with 0-3 R4b,
C6-C10 aryl substituted with 0-3 R4b, or
5 to 6 membered heterocycle substituted with 0-3 R4b;
R4a, at each occurrence, is independently selected from is H, F, Cl, CF3,
C3-C6 cycloalkyl substituted with 0-3 R4b,
phenyl substituted with 0-3 R4b, or
5 to 6 membered heterocycle substituted with 0-3 R4b;
R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
R5 is H;
C1-C4 alkyl substituted with 0-2 R5b;
C2-C4 alkenyl substituted with 0-2 R5b;
C2-C4 alkynyl substituted with 0-2 R5b;
C3-C6 cycloalkyl substituted with 0-2 R5c; or
phenyl substituted with 0-3 R5c;
R5a is H, methyl, ethyl, propyl, butyl, or allyl;
R5b, at each occurrence, is independently selected from:
H, methyl, ethyl, propyl, butyl, CF3, OR14,
C3-C6 cycloalkyl substituted with 0-2 R5c;
phenyl substituted with 0-3 R5c; or
5 to 6 membered heterocycle substituted with 0-2 R5c;
R5c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
alternatively, R5 and R5a may be combined to form a 3-7 membered carbocyclic ring substituted with 0-3 R5c;
W is a bond, xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94, xe2x80x94CH2CH2xe2x80x94 or xe2x80x94CH(CH3)CH2xe2x80x94;
X is a bond;
phenyl substituted with 0-2 RXb;
C3-C6 cycloalkyl substituted with 0-2 RXb; or
5 to 6 membered heterocycle substituted with 0-2 RXb;
RXb, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
Y is a bond, xe2x80x94CH2CH2xe2x80x94Vxe2x80x94, xe2x80x94CH2xe2x80x94Vxe2x80x94, or xe2x80x94Vxe2x80x94;
V is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S (xe2x95x90O)2xe2x80x94, xe2x80x94N(R19)xe2x80x94, xe2x80x94C(xe2x95x90O)NR19bxe2x80x94, xe2x80x94NR19bC(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90O)Oxe2x80x94, or xe2x80x94OC(xe2x95x90O)xe2x80x94;
Z is H;
C1-C8 alkyl substituted with 0-3 R12a;
C2-C4 alkenyl substituted with 0-3 R12a;
C2-C4 alkynyl substituted with 0-3 R12a;
C6-C10 aryl substituted with 0-4 R12a;
C3-C10 carbocycle substituted with 0-4 R12a; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12a; or
R12a, at each occurrence, is independently selected from
H, OH, Cl, F, Br, I, CN, NO2, NR15R16, xe2x80x94C(xe2x95x90O)NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, C1-C4 haloalkyl-Sxe2x80x94,
C1-C3 alkyl substituted with 0-1 R12c;
C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12b at each occurrence, is independently selected from H, OH, Cl, F, NR15R16 CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
R12c at each occurrence, is independently selected from
C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R11, at each occurrence, is independently selected from H,
C1-C4 alkoxy, Cl, F, NR18R19, C(xe2x95x90O)R17, C(xe2x95x90O)OR17, CF3;
C1-C4 alkyl substituted with 0-1 R11a;
phenyl substituted with 0-3 R11b;
C3-C6 carbocycle substituted with 0-3 R11b; or
5 to 6 membered heterocycle substituted with 0-3 R11b;
alternatively, two R11 substituents on the same or adjacent carbon atoms may be combined to form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or a benzo fused radical;
R11a, at each occurrence, is independently selected from H, C1-C4 alkyl, OR14, F, xe2x95x90O, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR1SR16, CF3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
R14 is H, phenyl, benzyl, C1-C4 alkyl, or C2-C4 alkoxyalkyl;
R15, at each occurrence, is independently selected from H, C1-C4 alkyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C4 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C4 alkyl);
R16, at each occurrence, is independently selected from H, OH, C1-C4 alkyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C4 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C4 alkyl);
R17 is H, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-trifluorophenyl, (4-fluorophenyl)methyl, (4-chlorophenyl)methyl, (4-methylphenyl)methyl, (4-trifluorophenyl)methyl, methyl, ethyl, propyl, butyl, methoxymethyl, methyoxyethyl, ethoxymethyl, or ethoxyethyl;
R18, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and
R19, at each occurrence, is independently selected from H, methyl, and ethyl;
R19b is H, mehyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, benzyl or phenethyl;
additionally, R18 and R19, when substituents on the same atom, may be combined to form a 3 to 7 membered heterocyclic ring.
[4] In another preferred embodiment the present invention provides a compound of Formula (Ia): 
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
ring B is selected from the group consisting of: -cyclopent-1,2-diyl-, -cyclopent-1,3-diyl-, -cyclohex-1,2-diyl-, -cyclohex-1,3-diyl-, -cyclohex-1,4-diyl-, -cyclohept-1,3-diyl-, -cyclopenten-3,5-diyl-, -phen-1,2-diyl-, -phen-1,3 -diyl-, -phen-1,4-diyl-, -pyrrolidin-1,4-diyl-, -pyrrolidin-2,4-diyl-, -piperidin-1,4-diyl-, -piperidin-1,3-diyl-, -thiophen-2,3-diyl-, and 
a bicyclic ring system selected from the group consisting of: 
a tricyclic ring system selected from the group consisting of: 
a tetracyclic ring system selected from the group consisting of: 
s is 0, 1, or 2;
R3 is xe2x80x94R4, xe2x80x94CH2xe2x80x94R4, or xe2x80x94CH2CH2xe2x80x94R4;
R3a is H;
alternatively, R3 and R3a may be combined to form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl moiety;
R4 is H, C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl;
R5 is C1-C4 alkyl substituted with 0-1 R5b;
C2-C4 alkenyl substituted with 0-1 R5b; or
C2-C4 alkynyl substituted with 0-1 R5b;
R5a is H;
R5b, at each occurrence, is independently selected from:
H, methyl, ethyl, propyl, butyl, CF3, OR14,
C3-C6 cycloalkyl substituted with 0-2 R5c;
phenyl substituted with 0-3 R5c; or
5 to 6 membered heterocycle substituted with 0-2 R5c;
alternatively, R5 and R5a may be combined to form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl ring;
W is a bond, xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94, xe2x80x94CH2CH2xe2x80x94 or xe2x80x94CH(CH3)CH2xe2x80x94;
X is a bond, phenyl, pyridyl, cyclopentyl, cyclohexyl, piperidinyl, or pyrrolidinyl;
Y is a bond, xe2x80x94CH2CH2xe2x80x94Vxe2x80x94, xe2x80x94CH2xe2x80x94Vxe2x80x94, or xe2x80x94Vxe2x80x94;
V is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94N(R19)xe2x80x94, xe2x80x94C(xe2x95x90O)NR19bxe2x80x94,
xe2x80x94NR19bC(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90O)Oxe2x80x94, or xe2x80x94OC(xe2x95x90O)xe2x80x94;
Z is H;
C1-C8 alkyl substituted with 0-3 R12a;
5 C2-C4 alkenyl substituted with 0-3 R12a;
C2-C4 alkynyl substituted with 0-3 R12a;
C6-C10 aryl substituted with 0-2 R12a;
C3-C10 carbocycle substituted with 0-4 R12a; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12a; or
R12a, at each occurrence, is independently selected from
H, OH, Cl, F, Br, I, CN, NO2, NR15R16, xe2x80x94C(xe2x95x90O)NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, C1-C4 haloalkyl-Sxe2x80x94,
C1-C3 alkyl substituted with 0-1 R12c;
C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
R12c, at each occurrence, is independently selected from
C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R11, at each occurrence, is independently selected from H, C1-C4 alkoxy, Cl, F, xe2x95x90O, NR18R19, C(xe2x95x90O)R17, C(xe2x95x90O)OR17, CF3; C1-C4 alkyl substituted with 0-1 R11a;
phenyl substituted with 0-3 R11b;
C3-C6 carbocycle substituted with 0-3 R11b; or
5 to 6 membered heterocycle substituted with 0-3 R11b;
alternatively, two R11 substituents on the same or adjacent carbon atoms may be combined to form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or a benzo fused radical;
R11a, at each occurrence, is independently selected from H, C1-C4 alkyl, OR14, F, xe2x95x90O, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
R14 is H, phenyl, benzyl, C1-C4 alkyl, or C2-C4 alkoxyalkyl;
R15, at each occurrence, is independently selected from H, C1-C4 alkyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C4 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C4 alkyl);
R16, at each occurrence, is independently selected from H, OH, C1-C4 alkyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C4 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C4 alkyl);
R17 is H, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-trifluorophenyl, (4-fluorophenyl)methyl, (4-chlorophenyl)methyl, (4-methylphenyl)methyl, (4-trifluorophenyl)methyl, methyl, ethyl, propyl, butyl, methoxymethyl, methyoxyethyl, ethoxymethyl, or ethoxyethyl;
R18, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and
R19, at each occurrence, is independently selected from H, methyl, and ethyl; R19b is H, mehyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, benzyl or phenethyl;
additionally, R18 and R19, when substituents on the same atom, may be combined to form a 3 to 7 membered heterocyclic ring.
[5] In another preferred embodiment the present invention provides a compound of Formula (Ic): 
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
ring B is selected from the group consisting of: 
R3 is xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94CH2CH2CH3, xe2x80x94CH2CH2CH2CH3, xe2x80x94CH2(CH3)2, xe2x80x94CH(CH3)CH2CH3, xe2x80x94CH2CH(CH3)2, xe2x80x94CH2C(CH3)3, xe2x80x94CHxe2x95x90CH2, xe2x80x94CH2CHxe2x95x90CH2, xe2x80x94CH2C(CH3)xe2x95x90CH2, xe2x80x94CH2CHxe2x95x90C(CH3)2, xe2x80x94CH2CH2CHxe2x95x90CH2, xe2x80x94CH2CH2C(CH3)xe2x95x90CH2, xe2x80x94CH2CH2CHxe2x95x90C(CH3)2, cis-CH2CHxe2x95x90CH(CH3), cis-CH2CH2CHxe2x95x90CH(CH3), trans-CH2CHxe2x95x90CH(CH3), trans-CH2CH2CHxe2x95x90CH(CH3), xe2x80x94Cxe2x89xa1CH, xe2x80x94CH2Cxe2x89xa1CH, or xe2x80x94CH2Cxe2x89xa1C(CH3);
R3a is H;
alternatively, R3 and R3a may be combined to form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl moiety;
R5 is xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94CH2CH2CH3, xe2x80x94CH2(CH3)2, xe2x80x94CH2CH2CH2CH3, xe2x80x94CH(CH3)CH2CH3, xe2x80x94CH2CH(CH3)2, xe2x80x94CH2C(CH3)3, xe2x80x94CH2CH2CH2CH2CH3, xe2x80x94CH(CH3)CH2CH2CH3, xe2x80x94CH2CH(CH3)CH2CH3, xe2x80x94CH2CH2CH(CH3)2, xe2x80x94CH(CH2CH3)2, xe2x80x94CHxe2x95x90CH2, xe2x80x94CH2CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CHCH3, cis-CH2CHxe2x95x90CH(CH3), trans-CH2CHxe2x95x90CH(CH3), xe2x80x94CH2CHxe2x95x90C(CH3)2, cis-CH2CHxe2x95x90CHCH2CH3, trans-CH2CHxe2x95x90CHCH2CH3, cis-CH2CH2CHxe2x95x90CH(CH3), trans-CH2CH2CHxe2x95x90CH(CH3), xe2x80x94Cxe2x89xa1CH, xe2x80x94CH2Cxe2x89xa1CH, xe2x80x94CH2Cxe2x89xa1C(CH3), xe2x80x94CH2CH2Cxe2x89xa1CH, or -CH2CH2Cxe2x89xa1C(CH3);
R5a is H;
alternatively, R5 and R5a may be combined to form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl ring;
Y is a bond, xe2x80x94CH2CH2xe2x80x94Vxe2x80x94, xe2x80x94CH2xe2x80x94Vxe2x80x94, or xe2x80x94Vxe2x80x94;
V is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S (xe2x95x90O)2xe2x80x94, xe2x80x94N(R19)xe2x80x94, xe2x80x94C(xe2x95x90O)NR19bxe2x80x94, xe2x80x94NR19bC(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90O)Oxe2x80x94, or xe2x80x94OC(xe2x95x90O)xe2x80x94;
Z is H;
C1-C4 alkyl substituted with 0-1 R12a;
C2-C4 alkenyl substituted with 0-1 Rl2a;
C2-C4 alkynyl substituted with 0-1 R12a;
phenyl substituted with 0-2 R12a;
C3-C6 cycloalkyl, selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; substituted with 0-2 R12a; or
5 to 10 membered heterocycle selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, pyrrolidinyl, piperidinyl, N-piperinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, morpholinyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl, and isoquinolinyl; wherein said 5 to 10 membered heterocycle is substituted with 0-2 R12a;
R12a, at each occurrence, is independently selected from
H, OH, Cl, F, Br, CN, NO2, NR15R16, xe2x80x94C(xe2x95x90O)NR15R16, CF3, acetyl, SCH3, SCF3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C1-C2 haloalkyl,
C1-C2 haloalkoxy,
C1-C3 alkyl substituted with R12c;
phenyl substituted with 0-3 R12b;
5 to 10 membered heterocycle selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, pyrrolidinyl, piperidinyl, N-piperinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, morpholinyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, lH-indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl, and isoquinolinyl; wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
R12c, at each occurrence, is independently selected from
phenyl substituted with 0-4 R12b;
C3-C10 cycloalkyl, selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; substituted with 0-4 R12b; or
5 to 10 membered heterocycle selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, pyrrolidinyl, piperidinyl, N-piperinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, morpholinyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl, and isoquinolinyl; wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R11, at each occurrence, is independently selected from H, Cl, F, NR18R19, methyl, ethyl, methoxy, ethoxy, phenyl, benzyl, phenethyl, 4-F-phenyl, (4-F-phenyl)CH2xe2x80x94, (4-F-phenyl)CH2CH2xe2x80x94, 4-Cl-phenyl, (4-Cl-phenyl)CH2xe2x80x94, (4-Cl-phenyl)CH2CH2xe2x80x94, 4xe2x80x94CH3-phenyl, (4-CH3-phenyl)CH2xe2x80x94, (4-CH3-phenyl)CH2CH2xe2x80x94, 4-CF3-phenyl, (4-CF3-phenyl)CH2xe2x80x94, or (4-CF3-phenyl)CH2CH2xe2x80x94; and
R15, at each occurrence, is independently selected from
H, methyl, ethyl, propyl, butyl, benzyl, phenethyl,
methyl-C(xe2x95x90O)xe2x80x94, ethyl-C(xe2x95x90O)xe2x80x94, propyl-C(xe2x95x90O)xe2x80x94,
butyl-C(xe2x95x90O)xe2x80x94, methyl-S(xe2x95x90O)2xe2x80x94, ethyl-S(xe2x95x90O)2xe2x80x94,
propyl-S(xe2x95x90O)2xe2x80x94, and butyl-S(xe2x95x90O)2xe2x80x94;
R16, at each occurrence, is independently selected from
H, OH, methyl, ethyl, propyl, butyl, benzyl, phenethyl, methyl-C(xe2x95x90O)xe2x80x94, ethyl-C(xe2x95x90O)xe2x80x94, propyl-C(xe2x95x90O)xe2x80x94,
butyl-C(xe2x95x90O)xe2x80x94, methyl-S(xe2x95x90O)2xe2x80x94, ethyl-S(xe2x95x90O)2xe2x80x94,
propyl-S(xe2x95x90O)2xe2x80x94, and butyl-S(xe2x95x90O)2xe2x80x94;
R18, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and
R19, at each occurrence, is independently selected from H, methyl, and ethyl;
R19b is H, mehyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, benzyl or phenethyl;
additionally, R18 and R19, when substituents on the same atom, may be combined to form a 3 to 7 membered heterocyclic ring selected from pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, and morpholinyl.
[6] In another embodiment the present invention provides a compound of Formula (I): 
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
Q is NH2;
ring B is cycloalkyl group of 3 to 8 carbon atoms wherein the cycloalkyl group is saturated, partially saturated or unsaturated; a heterocycle of 3 to 8 atoms containing a heteroatom selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, and xe2x80x94N(R10)xe2x80x94; 
s is 0, 1, 2, 3, 4, 5, or 6;
R3 is xe2x80x94(CR7R7a)nxe2x80x94R4,
xe2x80x94(CR7R7a)nxe2x80x94Sxe2x80x94(CR7R7a)mxe2x80x94R4,
xe2x80x94(CR7R7a)nxe2x80x94Oxe2x80x94(CR7R7a)mxe2x80x94R4, or
xe2x80x94(CR7R7a)nxe2x80x94N(R7b)xe2x80x94(CR7R7a)mxe2x80x94R4;
n is 0, 1, or 2;
m is 0, 1, or 2;
R3a is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, or butoxy;
R4 is H, OH, OR14a,
C1-C4 alkyl substituted with 0-2 R4a,
C2-C4 alkenyl substituted with 0-2 R4a,
C2-C4 alkynyl substituted with 0-2 R4a,
C3-C6 cycloalkyl substituted with 0-3 R4b,
C6-C10 aryl substituted with 0-3 R4b, or
5 to 10 membered heterocycle substituted with 0-3 R4b;
R4a, at each occurrence, is independently selected from is H, F, Cl, Br, I, CF3,
C3-C10 carbocycle substituted with 0-3 R4b,
C6-C10 aryl substituted with 0-3 R4b, or
5 to 10 membered heterocycle substituted with 0-3 R4b;
R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
R5 is H, OR14;
C1-C6 alkyl substituted with 0-3 R5b;
C2-C6 alkenyl substituted with 0-3R5b;
C2-C6 alkynyl substituted with 0-3 R5b;
C3-C10 carbocycle substituted with 0-3 R5c;
C6-C10 aryl substituted with 0-3 RsC; or
5 to 10 membered heterocycle substituted with 0-3R5c;
R5a is H, OH, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, or C2-C4 alkenyloxy; R5b, at each occurrence, is independently selected from:
H, C1-C6 alkyl, CF3, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16;
C3-C10 carbocycle substituted with 0-3 R5c;
C6-C10 aryl substituted with 0-3 R5C; or
5 to 10 membered heterocycle substituted with 0-3 R5c;
R5c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
R6 is H, methyl, or ethyl;
R7, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, and C1-C4 alkyl;
R7a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, phenyl and C1-C4 alkyl; R7b is independently selected from H, methyl, ethyl, propyl, and butyl;
W is xe2x80x94(CR8R8a)pxe2x80x94;
p is 0, 1, or 2;
R8 and R8a, at each occurrence, are independently selected from H, F, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl and C3-C6 cycloalkyl;
X is a bond;
C6-C10 aryl substituted with 0-3 RXb;
C3-C10 carbocycle substituted with 0-2 RXb; or 5 to 10 membered heterocycle substituted with 0-2 RXb;
RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; Y is a bond or xe2x80x94(CR9R9a)txe2x80x94Vxe2x80x94(CR9R9a)uxe2x80x94;
t is 0, 1, or 2;
u is 0, 1, or 2;
R9 and R9a, at each occurrence, are independently selected from H, F, C1-C4 alkyl or C3-C6 cycloalkyl;
V is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94N(R19)xe2x80x94, xe2x80x94C(xe2x95x90O)NR19bxe2x80x94, xe2x80x94NR19bC(xe2x95x90O)xe2x80x94, xe2x80x94NR19bS(xe2x95x90O)2xe2x80x94, xe2x80x94S(xe2x95x90O)2NR19bxe2x80x94, xe2x80x94NR19bs (xe2x95x90O)xe2x80x94, or xe2x80x94S(xe2x95x90O)NR19bxe2x80x94;
Z is C1-C3 alkyl substituted with 1-2 R12;
C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle substituted with 0-3 R12b;
R12 is C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle substituted with 0-3 R12b;
R12b at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
R10 is H, C(xe2x95x90O)R17, C(xe2x95x90O)OR17, C(xe2x95x90O)NR18R19, S(xe2x95x90O)2NR18R19, S(xe2x95x90O)2R17;
C1-C6 alkyl substituted with 0-1 R10a;
C6-C10 aryl substituted with 0-4 R10b;
C3-C10 carbocycle substituted with 0-3 R10b; or
5 to 10 membered heterocycle optionally substituted with 0-3 R10b;
R10a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, CF3, or phenyl substituted with 0-4 R10b;
R10b, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, or CF3; R11, at each occurrence, is independently selected from
C1-C4 alkoxy, Cl, F, NR18R19, C(xe2x95x90O)R17, C(xe2x95x90O)OR17, C(xe2x95x90O)NR18R19, S(xe2x95x90O)2NR18R19, CF3;
C1-C6 alkyl substituted with 0-1 R11a;
C6-C10 aryl substituted with 0-3 R11b;
C3-C10 carbocycle substituted with 0-3 R11b; or
5 to 10 membered heterocycle substituted with 0-3 R11b;
alternatively, two R 11 substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle or a benzo fused radical;
R11a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
R14 is H, phenyl, benzyl, C1-C6 alkyl, or C2-C6 alkoxyalkyl;
R15, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C6 alkyl);
R16, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C6 alkyl);
R17 is H, aryl, (aryl)CH2xe2x80x94, C1-C6 alkyl, or C2-C6 alkoxyalkyl;
R18, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C6 alkyl); and
R19, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, phenyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C6 alkyl); and
R19b is H, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, benzyl or phenethyl.
[7] In another preferred embodiment the present invention provides a compound of Formula (Ia) wherein:
R3 is xe2x80x94(CR7R7a)nxe2x80x94R4,
xe2x80x94(CR7R7a)nxe2x80x94Sxe2x80x94(CR7R7a)mxe2x80x94R4,
xe2x80x94(CR7R7a)nxe2x80x94Oxe2x80x94(CR7R7a)mxe2x80x94R4, or
xe2x80x94(CR7R7a)nxe2x80x94N(R7b)xe2x80x94(CR7R7a)mxe2x80x94R4;
n is 0 or 1;
m is 0 or 1;
R3a is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, or butoxy;
R4is H, OH,
C1-C4 alkyl substituted with 0-2 R4a,
C2-C4 alkenyl substituted with 0-2 R4a,
C2-C4 alkynyl substituted with 0-1 R4a,
C3-C6 cycloalkyl substituted with 0-3 R4b,
C6-C10 aryl substituted with 0-3 R4b, or
5 to 10 membered heterocycle substituted with 0-3 R4b;
R4a, at each occurrence, is independently selected from is H, F, Cl, CF3,
C3-C6 cycloalkyl substituted with 0-3 R4b,
phenyl substituted with 0-3 R4b, or
5 to 6 membered heterocycle substituted with 0-3 R4b;
R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
R5 is H, OR14;
C1-C4 alkyl substituted with 0-3 R5b;
C2-C4 alkenyl substituted with 0-2 R5b; or
C2-C4 alkynyl substituted with 0-2 R5b;
R5a is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, or allyl;
R5b, at each occurrence, is independently selected from:
H, methyl, ethyl, propyl, butyl, CF3, OR14, xe2x95x90O;
C3-C6 cycloalkyl substituted with 0-2 R5c;
phenyl substituted with 0-3 R5c; or
5 to 6 membered heterocycle substituted with 0-2 R5C;
R5c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
R6 is H;
R7, at each occurrence, is independently selected from H, F, CF3, methyl, and ethyl;
R7a, at each occurrence, is independently selected from H, F, CF3, methyl, and ethyl;
R7b is independently selected from H, methyl, and ethyl;
W is a bond, xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94, xe2x80x94CH2CH2xe2x80x94 or xe2x80x94CH(CH3)CH2xe2x80x94;
X is a bond;
phenyl substituted with 0-2 RXb;
C3-C6 cycloalkyl substituted with 0-2 RXb; or
5 to 6 membered heterocycle substituted with 0-2 RXb;
RXb, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
Y is a bond, xe2x80x94CH2xe2x80x94Vxe2x80x94, xe2x80x94Vxe2x80x94, or xe2x80x94Vxe2x80x94CH2xe2x80x94;
V is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S (xe2x95x90O)2xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94N(CH3)xe2x80x94, or xe2x80x94N(CH2CH3)xe2x80x94,
Z is C1-C2 alkyl substituted with 1-2 R12;
C6-C10 aryl substituted with 0-4 R12b;
C3-C6 carbocycle substituted with 0-3 R12b; or
5 to 10 membered heterocycle substituted with 0-3 R12b;
R12 is C6-C10 aryl substituted with 0-4 R12b;
C3-C6 carbocycle substituted with 0-3 R12b; or
5 to 10 membered heterocycle substituted with 0-3 R12b;
R12b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
R10 is H, C(xe2x95x90O)R17, C(xe2x95x90O)OR17;
C1-C4 alkyl substituted with 0-1 R10a;
phenyl substituted with 0-4 R10b;
C3-C6 carbocycle substituted with 0-3 R10b; or
5 to 6 membered heterocycle optionally substituted with 0-3 R10b;
R10a, at each occurrence, is independently selected from H, C1-C4 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, CF3, or phenyl substituted with 0-4 R10b;
R10b, at each occurrence, is independently selected from H, OH, C1-C4 alkyl, C1-C3 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, or CF3;
R11, at each occurrence, is independently selected from
C1-C4 alkoxy, Cl, F, xe2x95x90O, NR18R19, C(xe2x95x90O)R17, C(xe2x95x90O)OR17, CF3;
C1-C4 alkyl substituted with 0-1 R11a;
phenyl substituted with 0-3 R11b;
C3-C6 carbocycle substituted with 0-3 R11b; or 5 to 6 membered heterocycle substituted with 0-3 R11b;
alternatively, two R11 substituents on the same or adjacent carbon atoms may be combined to form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or a benzo fused radical;
R11a, at each occurrence, is independently selected from H, C1-C4 alkyl, OR14, F, xe2x95x90O, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
R14 is H, phenyl, benzyl, C1-C4 alkyl, or C2-C4 alkoxyalkyl;
R15, at each occurrence, is independently selected from H, C1-C4 alkyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C4 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C4 alkyl);
R16, at each occurrence, is independently selected from H, OH, C1-C4 alkyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C4 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C4 alkyl);
R17 is H, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-trifluorophenyl, (4-fluorophenyl)methyl, (4-chlorophenyl)methyl, (4-methylphenyl)methyl, (4-trifluorophenyl)methyl, methyl, ethyl, propyl, butyl, methoxymethyl, methyoxyethyl, ethoxymethyl, or ethoxyethyl;
R18, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and
R19, at each occurrence, is independently selected from H, methyl, and ethyl.
[8] In another preferred embodiment the present invention provides a compound of Formula (Ib): 
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R3 is xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94CH2CH2CH3, xe2x80x94CH2CH2CH2CH3, xe2x80x94CH2(CH3)2, xe2x80x94CH(CH3)CH2CH3, xe2x80x94CH2CH(CH3)2, xe2x80x94CH2C(CH3)3, xe2x80x94CF3, xe2x80x94CH2CF3, xe2x80x94CH2CH2CF3, xe2x80x94CH2CH2CH2CF3, xe2x80x94CHxe2x95x90CH2, xe2x80x94CH2CHxe2x95x90CH2, xe2x80x94CH2C(CH3)xe2x95x90CH2, xe2x80x94CH2CHxe2x95x90C(CH3)2, xe2x80x94CH2CH2CHxe2x95x90CH2, xe2x80x94CH2CH2C(CH3)xe2x95x90CH2, xe2x80x94CH2CH2CHxe2x95x90C(CH3)2, cis-CH2CHxe2x95x90CH(CH3), cis-CH2CH2CHxe2x95x90CH(CH3), trans-CH2CHxe2x95x90CH(CH3), trans-CH2CH2CHxe2x95x90CH(CH3); xe2x80x94Cxe2x89xa1CH, xe2x80x94CH2Cxe2x89xa1CH, xe2x80x94CH2Cxe2x89xa1C(CH3), cyclopropyl-CH2xe2x80x94, cyclobutyl-CH2xe2x80x94, cyclopentyl-CH2xe2x80x94, cyclohexyl-CH2xe2x80x94, cyclopropyl-CH2CH2xe2x80x94, cyclobutyl-CH2CH2xe2x80x94, cyclopentyl-CH2CH2xe2x80x94, cyclohexyl-CH2CH2xe2x80x94, phenyl-CH2xe2x80x94, (2-F-phenyl)CH2xe2x80x94, (3-F-phenyl)CH2xe2x80x94, (4-F-phenyl)CH2xe2x80x94, (2-Cl-phenyl)CH2xe2x80x94, (3-Cl-phenyl)CH2xe2x80x94, (4-Cl-phenyl)CH2xe2x80x94, (2,3-diF-phenyl)CH2xe2x80x94, (2,4-diF-phenyl)CH2xe2x80x94, (2,5-diF-phenyl)CH2xe2x80x94, (2,6-diF-phenyl)CH2xe2x80x94, (3,4-diF-phenyl)CH2xe2x80x94, (3,5-diF-phenyl)CH2xe2x80x94, (2,3-diCl-phenyl)CH2xe2x80x94, (2,4-diCl-phenyl)CH2xe2x80x94, (2,5-diCl-phenyl)CH2xe2x80x94, (2,6-diCl-phenyl)CH2xe2x80x94, (3,4-diCl-phenyl)CH2xe2x80x94, (3,5-diCl-phenyl)CH2xe2x80x94, (3-F-4-Cl-phenyl)CH2xe2x80x94, (3-F-5-Cl-phenyl)CH2xe2x80x94, (3-Cl-4-F-phenyl)CH2xe2x80x94, phenyl-CH2CH2xe2x80x94, (2-F-phenyl)CH2CH2xe2x80x94, (3-F-phenyl)CH2CH2xe2x80x94, (4-F-phenyl)CH2CH2xe2x80x94, (2-Cl-phenyl)CH2CH2xe2x80x94, (3-Cl-phenyl)CH2CH2xe2x80x94, (4-Cl-phenyl)CH2CH2xe2x80x94, (2,3-diF-phenyl)CH2CH2xe2x80x94, (2,4-diF-phenyl)CH2CH2xe2x80x94, (2,5-diF-phenyl)CH2CH2xe2x80x94, (2,6-diF-phenyl)CH2CH2xe2x80x94, (3,4-diF-phenyl)CH2CH2xe2x80x94, (3,5-diF-phenyl)CH2CH2xe2x80x94, (2,3-diCl-phenyl)CH2CH2xe2x80x94, (2,4-diCl-phenyl)CH2CH2xe2x80x94, (2,5-diCl-phenyl)CH2CH2xe2x80x94, (2,6-diCl-phenyl)CH2CH2xe2x80x94, (3,4-diCl-phenyl)CH2CH2xe2x80x94, (3,5-diCl-phenyl)CH2CH2xe2x80x94, (3-F-4-Cl-phenyl)CH2CH2xe2x80x94, or (3-F-5-Cl-phenyl)CH2CH2xe2x80x94;
R5 is -CH3, xe2x80x94CH2CH3, xe2x80x94CH2CH2CH3, xe2x80x94CH2(CH3)2, xe2x80x94CH2CH2CH2CH3, xe2x80x94CH(CH3)CH2CH3, xe2x80x94CH2CH(CH3)2, xe2x80x94CH2C(CH3)3, xe2x80x94CH2CH2CH2CH2CH3, xe2x80x94CH(CH3)CH2CH2CH3, xe2x80x94CH2CH(CH3)CH2CH3, xe2x80x94CH2CH2CH(CH3)2, xe2x80x94CH(CH2CH3)2, -CF3, xe2x80x94CH2CF3, xe2x80x94CH2CH2CF3, xe2x80x94CH2CH2CH2CF3, xe2x80x94CH2CH2CH2CH2CF3, xe2x80x94CHxe2x95x90CH2, xe2x80x94CH2CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CHCH3, cis-CH2CHxe2x95x90CH(CH3), trans-CH2CHxe2x95x90CH(CH3), trans-CH2CHxe2x95x90CH(C6H5), xe2x80x94CH2CHxe2x95x90C(CH3)2, cis-CH2CHxe2x95x90CHCH2CH3, trans-CH2CHxe2x95x90CHCH2CH3, cis-CH2CH2CHxe2x95x90CH(CH3), trans-CH2CH2CHxe2x95x90CH(CH3), trans-CH2CHxe2x95x90CHCH2(C6H5), xe2x80x94Cxe2x89xa1CH, xe2x80x94CH2Cxe2x89xa1CH, xe2x80x94CH2Cxe2x89xa1C(CH3), xe2x80x94CH2Cxe2x89xa1C(C6H5), xe2x80x94CH2CH2Cxe2x89xa1CH, xe2x80x94CH2CH2Cxe2x89xa1C(CH3), xe2x80x94CH2CH2Cxe2x89xa1C(C6H5), xe2x80x94CH2CH2CH2Cxe2x89xa1CH, xe2x80x94CH2CH2CH2Cxe2x89xa1C(CH3), xe2x80x94CH2CH2CH2Cxe2x89xa1C(C6H5), cyclopropyl-CH2xe2x80x94, cyclobutyl-CH2xe2x80x94, cyclopentyl-CH2xe2x80x94, cyclohexyl-CH2xe2x80x94, (2-CH3-cyclopropyl)CH2xe2x80x94, (3-CH3-cyclobutyl)CH2xe2x80x94, cyclopropyl-CH2CH2xe2x80x94, cyclobutyl-CH2CH2xe2x80x94, cyclopentyl-CH2CH2xe2x80x94, cyclohexyl-CH2CH2xe2x80x94, (2-CH3-cyclopropyl)CH2CH2xe2x80x94, (3-CH3-cyclobutyl)CH2CH2xe2x80x94, phenyl-CH2xe2x80x94, (2-F-phenyl)CH2xe2x80x94, (3-F-phenyl)CH2xe2x80x94, (4-F-phenyl)CH2xe2x80x94, furanyl-CH2xe2x80x94, thienyl-CH2xe2x80x94, pyridyl-CH2xe2x80x94, 1-imidazolyl-CH2xe2x80x94, oxazolyl-CH2xe2x80x94, isoxazolyl-CH2xe2x80x94, phenyl-CH2CH2xe2x80x94, (2-F-phenyl)CH2CH2xe2x80x94, (3-F-phenyl)CH2CH2xe2x80x94, (4-F-phenyl)CH2CH2xe2x80x94, furanyl-CH2CH2xe2x80x94, thienyl-CH2CH2xe2x80x94, pyridyl-CH2CH2xe2x80x94, 1-imidazolyl-CH2CH2xe2x80x94, oxazolyl-CH2CH2xe2x80x94, or isoxazolyl-CH2CH2xe2x80x94;
W is a bond, xe2x80x94CH2xe2x80x94, or xe2x80x94CH(CH3)xe2x80x94;
X is a bond; 
Y is a bond, xe2x80x94CH2xe2x80x94Vxe2x80x94, xe2x80x94Vxe2x80x94, or xe2x80x94Vxe2x80x94CH2xe2x80x94;
V is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94N(CH3)xe2x80x94,
Z is phenyl 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl, 3,5-diF-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl, 2,5-diCl-phenyl, 2,6-diCl-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Cl-4-F-phenyl, 2-MeO-phenyl, 3-MeO-phenyl, 4-MeO-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-MeS-phenyl, 3-MeS-phenyl, 4-MeS-phenyl, 2-CF3O-phenyl, 3-CF3O-phenyl, 4-CF3O-phenyl, furanyl, thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl, 4-Me-pyridyl, 1-imidazolyl, oxazolyl, isoxazolyl, 1-benzimidazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholino,N-piperinyl, phenyl-CH2xe2x80x94, (2-F-phenyl)CH2xe2x80x94, (3-F-phenyl)CH2xe2x80x94, (4-F-phenyl)CH2xe2x80x94, (2-Cl-phenyl)CH2xe2x80x94, (3-Cl-phenyl)CH2xe2x80x94, (4-Cl-phenyl)CH2xe2x80x94, (2,3-diF-phenyl)CH2xe2x80x94, (2,4-diF-phenyl)CH2xe2x80x94, (2,5-diF-phenyl)CH2xe2x80x94, (2,6-diF-phenyl)CH2xe2x80x94, (3,4-diF-phenyl)CH2xe2x80x94, (3,5-diF-phenyl)CH2xe2x80x94, (2,3-diCl-phenyl)CH2xe2x80x94, (2,4-diCl-phenyl)CH2xe2x80x94, (2,5-diCl-phenyl)CH2xe2x80x94, (2,6-diCl-phenyl)CH2xe2x80x94, (3,4-diCl-phenyl)CH2xe2x80x94, (3,5-diCl-phenyl)CH2xe2x80x94, (3-F-4-Cl-phenyl)CH2xe2x80x94, (3-F-5-Cl-phenyl)CH2xe2x80x94, (3-Cl-4-F-phenyl)CH2xe2x80x94, (2-MeO-phenyl)CH2xe2x80x94, (3-MeO-phenyl)CH2xe2x80x94, (4-MeO-phenyl)CH2xe2x80x94, (2-Me-phenyl)CH2xe2x80x94, (3-Me-phenyl)CH2xe2x80x94, (4-Me-phenyl)CH2xe2x80x94, (2-MeS-phenyl)CH2xe2x80x94, (3-MeS-phenyl)CH2xe2x80x94, 4-MeS-phenyl)CH2xe2x80x94, (2-CF3O-phenyl)CH2xe2x80x94, (3-CF3O-phenyl)CH2xe2x80x94, (4-CF3O-phenyl)CH2xe2x80x94, (furanyl)CH2xe2x80x94, (thienyl)CH2xe2x80x94, (pyridyl)CH2xe2x80x94, (2-Me-pyridyl)CH2xe2x80x94, (3-Me-pyridyl)CH2xe2x80x94, (4-Me-pyridyl)CH2xe2x80x94, (1-imidazolyl)CH2xe2x80x94, (oxazolyl)CH2xe2x80x94, (isoxazolyl)CH2xe2x80x94, (1-benzimidazolyl)CH2xe2x80x94, (cyclopropyl)CH2xe2x80x94, (cyclobutyl)CH2xe2x80x94, (cyclopentyl)CH2xe2x80x94, (cyclohexyl)CH2xe2x80x94, (morpholino)CH2xe2x80x94, (N-pipridinyl)CH2xe2x80x94, phenyl-CH2CH2xe2x80x94, (phenyl)2CHCH2xe2x80x94, (2-F-phenyl)CH2CH2xe2x80x94, (3-F-phenyl)CH2CH2xe2x80x94, (4-F-phenyl)CH2CH2xe2x80x94, (2-Cl-phenyl)CH2CH2xe2x80x94, (3-Cl-phenyl)CH2CH2xe2x80x94, (4-Cl-phenyl)CH2CH2xe2x80x94, (2,3-diF-phenyl)CH2CH2xe2x80x94, (2,4-diF-phenyl)CH2CH2xe2x80x94, (2,5-diF-phenyl)CH2CH2xe2x80x94, (2,6-diF-phenyl)CH2CH2xe2x80x94, (3,4-diF-phenyl)CH2CH2xe2x80x94, (3,5-diF-phenyl)CH2CH2xe2x80x94, (2,3-diCl-phenyl)CH2CH2xe2x80x94, (2,4-diCl-phenyl)CH2CH2xe2x80x94, (2,5-diCl-phenyl)CH2CH2xe2x80x94, (2,6-diCl-phenyl)CH2CH2xe2x80x94, (3,4-diCl-phenyl)CH2CH2xe2x80x94, (3,5-diCl-phenyl)CH2CH2xe2x80x94, (3-F-4-Cl-phenyl)CH2CH2xe2x80x94, (3-F-5-Cl-phenyl)CH2CH2xe2x80x94, (3-Cl-4-F-phenyl)CH2CH2xe2x80x94, (2-MeO-phenyl)CH2CH2xe2x80x94, (3-MeO-phenyl)CH2CH2xe2x80x94, (4-MeO-phenyl)CH2CH2xe2x80x94, (2-Me-phenyl)CH2CH2xe2x80x94, (3-Me-phenyl)CH2CH2xe2x80x94, (4-Me-phenyl)CH2CH2xe2x80x94, (2-MeS-phenyl)CH2CH2xe2x80x94, (3-MeS-phenyl)CH2CH2xe2x80x94, (4-MeS-phenyl)CH2CH2xe2x80x94, (2-CF3O-phenyl)CH2CH2xe2x80x94, (3-CF3O-phenyl)CH2CH2xe2x80x94, (4-CF3O-phenyl)CH2CH2xe2x80x94, (furanyl)CH2CH2xe2x80x94, (thienyl)CH2CH2xe2x80x94, (pyridyl)CH2CH2xe2x80x94, (2-Me-pyridyl)CH2CH2xe2x80x94, (3-Me-pyridyl)CH2CH2xe2x80x94, (4-Me-pyridyl)CH2CH2xe2x80x94, (imidazolyl)CH2CH2xe2x80x94, (oxazolyl)CH2CH2xe2x80x94, (isoxazolyl)CH2CH2xe2x80x94, (benzimidazolyl)CH2CH2xe2x80x94,(cyclopropyl)CH2CH2xe2x80x94, (cyclobutyl)CH2CH2xe2x80x94,(cyclopentyl)CH2CH2xe2x80x94, (cyclohexyl)CH2CH2xe2x80x94, (morpholino)CH2CH2xe2x80x94, (N-pipridinyl)CH2CH2xe2x80x94, methyl, ethyl, i-propyl, n-propyl, n-butyl, i-butyl, s-butyl, t-butyl, or allyl;
R10 is H, methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl, (4-F-phenyl)CH2xe2x80x94, (4-F-phenyl)CH2CH2xe2x80x94, 4-Cl-phenyl, (4-Cl-phenyl)CH2xe2x80x94, (4-Cl-phenyl)CH2CH2xe2x80x94, 4-CH3-phenyl, (4-CH3-phenyl)CH2xe2x80x94, (4-CH3-phenyl)CH2CH2xe2x80x94, 4-CF3-phenyl, (4-CF3-phenyl)CH2xe2x80x94, or (4-CF3-phenyl)CH2CH2xe2x80x94;
R11, at each occurrence, is independently selected from H, methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl, (4-F-phenyl)CH2xe2x80x94, (4-F-phenyl)CH2CH2xe2x80x94, 4-Cl-phenyl, (4-Cl-phenyl)CH2xe2x80x94, (4-Cl-phenyl)CH2CH2xe2x80x94, 4-CH3-phenyl, (4-CH3-phenyl)CH2xe2x80x94, (4-CH3-phenyl)CH2CH2xe2x80x94, 4-CF3-phenyl, (4-CF3-phenyl)CH2xe2x80x94, or (4-CF3-phenyl)CH2CH2xe2x80x94; and
alternatively, two R11 substituents on the same or adjacent carbon atoms may be combined to form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or a benzo fused radical.
[9] In another preferred embodiment the present invention provides a compound of Formula (Ib) wherein:
ring B, along with up to 2 R11s, is 
wherein ring B is further substituted with 0, 1, 2, 3, or 4 R11.
[10] In another preferred embodient the present invention provides a compound selected from:
(2R,3S)-3-allyl-2-isobutyl-N1-(4-butyl-3-oxo-2,3,4,8,9,10-hexahydronaphtho[1,8-ef] [1,4]diazepin-2-yl)butanediamide;
(2R,3S)-3-allyl-2-isobutyl-N1-(4-methyl-3-oxo-2,3,4,8,9,10-hexahydronaphtho[1,8-ef] [1,4]diazepin-2-yl)butanediamide;
(2R, 3S)-3-allyl-2-isobutyl-N1-(4-(pyrid-2-ylmethyl)-3-oxo-2,3,4,8,9,10-hexahydronaphtho[1,8-ef] [1,4]diazepin-2-yl)butanediamide;
(2R, 3S)-3-allyl-2-isobutyl-N1-(4-(2-(diethylamino)ethyl)-3-oxo-2,3,4,8,9,10-hexahydronaphtho[1,8-ef] [1,4]diazepin-2-yl)butanediamide;
N1-(2-benzylcarbamoyl-4-oxo-1,2,4,5,6,7-hexahydro-azepino[3,2,1-hi]indol-5-yl)-2-isobutyl-3-propyl-succinamide;
N1-[2-(1-benzyl-pyrrolidin-3-ylcarbamoyl)-4-oxo-1,2,4,5,6,7-hexahydro-azepino[3,2,1-hi] indol-5-yl]-2-isobutyl-3-propyl-succinamide;
N1-[2-(1-benzyl-pyrrolidin-3-ylcarbamoyl)-4-oxo-1,2,4,5,6,7-hexahydro-azepino[3,2,1-hi]indol-5-yl]-2-isobutyl-3-propyl-succinamide;
2-isobutyl-N1-[2-(4-methoxy-benzylcarbamoyl)-4-oxo-1,2,4,5,6,7-hexahydro-azepino[3,2,1-hi]indol-5-yl]-3-propyl-succinamide;
2-isobutyl-N 1-[2-(3-methoxy-benzylcarbamoyl)-4-oxo-1,2,4,5,6,7-hexahydro-azepino[3,2,1-hi]indol-5-yl]-3-propyl-succinamide;
N1-[2-(cyclohexylmethyl-carbamoyl)-4-oxo-1,2,4,5,6,7-hexahydro-azepino[3,2,1-hi]indol-5-yl]-2-isobutyl-3-propyl-succinamide;
2-isobutyl-N1-(2-isopropylcarbamoyl-4-oxo-1,2,4,5,6,7-hexahydro-azepino[3,2,1-hi]indol-5-yl)-3-propyl-succinamide;
2-isobutyl-N 1-(4-oxo-2-phenylcarbamoyl-1,2,4,5,6,7-hexahydro-azepino[3,2,1-hi]indol-5-yl)-3-propyl-succinamide;
(2R,3S)-3-allyl-N1-[(7S)-2-benzyl-6-oxo-1,2,3,4,6,7,8,10a -octahydropyrazino[1,2-a]azepin-7-yl]-2-isobutylbutanediamide;
N1-(1,5-dioxo-octahydro-pyrrolo[1,2-a] [1,4]diazepin-4-yl)-2-isobutyl-3-propyl-succinamide;
N1-(2-benzyloxy-5-oxo-2,3,5,6,7,9a-hexahydro-1H-pyrrolo[1,2-a]azepin-6-yl)-2-isobutyl-3-propyl-succinamide;
N1-(2-benzyloxy-5-oxo-octahydro-pyrrolo[1,2-a]azepin-6-yl)-2-isobutyl-3-propyl-succinamide;
N1-(2-hydroxy-5-oxo-octahydro-pyrrolo[1,2-a]azepin-6-yl)-2-isobutyl-3-propyl-succinamide;
3-allyl-N1-[3 -(4-bromo-phenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-yl]-2-isobutyl-succinamide;
3-allyl-N1-[3-(4-phenyl-phenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-yl]-2-isobutyl-succinamide;
3-allyl-N1-[3-(4-benzofuran-2-yl-phenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-yl]-2-isobutyl-succinamide;
3-allyl-N1-[3-(4-(4-chloro-phenyl)-phenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-yl]-2-isobutyl-succinamide;
3-allyl-N1-[3-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]zepin-9-yl]-2-isobutyl-succinamide;
3-allyl-N1-[3-(3-bromo-phenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-yl]-2-isobutyl-succinamide;
3-allyl-N1-[3-(3-phenyl-phenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-yl]-2-isobutyl-succinamide; and
3-allyl-N1-[3-(3-benzofuran-2-yl-phenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-yl]-2-isobutyl-succinamide.
In another preferred embodiment of the present invention, Q is NH2.
In another preferred embodiment
R3 is R4,
R3a is H, methyl, ethyl, propyl, or butyl;
R4 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl R5 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl
R5a is H, methyl, ethyl, propyl, or butyl; and
the total number of carbon atoms in R3, R3a, R5 and R5a equals seven or more.
In another preferred embodiment
R3 is R4;
R3a is H;
R4 is C1-C4 alkyl substituted with 1-2 R4a,
R4a, at each occurrence, is independently selected from
C3-C6 cycloalkyl substituted with 0-3 R4b,
phenyl substituted with 0-3 R4b, or
5 to 6 membered heterocycle substituted with 0-3 R4b;
R4b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
R5 is C2-C4 alkyl substituted with 0-3 R5b;
C2-C4 alkenyl substituted with 0-2 R5b; or
C2-C4 alkynyl substituted with 0-2 R5b;
R5b, at each occurrence, is independently selected from:
H, methyl, ethyl, propyl, butyl, CF3, OR14, xe2x95x90O;
C3-C6 cycloalkyl substituted with 0-2 R5c;
phenyl substituted with 0-3 R5c; or
5 to 6 membered heterocycle substituted with 0-2 R5c; and
R5c, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy.
In another preferred embodiment
R3 is R4;
R3a is H;
R4 is C2-C4 alkyl substituted with 0-2 R4a,
C2-C4 alkenyl substituted with 0-2 R4a,
C2-C4 alkynyl substituted with 0-2 R4a,
R4a, at each occurrence, is independently selected from is H, F, CF3,
C3-C6 cycloalkyl substituted with 0-3 R4b,
phenyl substituted with 0-3 R4b, or
5 to 6 membered heterocycle substituted with 0-3 R4b;
R4b, at each occurrence, is independently selected from H, OH, Cl, F, NR15Rl6, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
R5 is C1-C4 alkyl substituted with 1-2 R5b;
R5b, at each occurrence, is independently selected from:
C3-C6 cycloalkyl substituted with 0-2 R5c;
phenyl substituted with 0-3 R5c; or
5 to 6 membered heterocycle substituted with 0-2 R5c; and
R5c, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy.
In another preferred embodiment
W is xe2x80x94(CH2)pxe2x80x94;
p is 1, 2, or 3;
X is a bond;
phenyl substituted with 0-2 RXb;
C3-C6 cycloalkyl substituted with 0-2 RXb; or
5 to 6 membered heterocycle substituted with 0-2 RXb;
wherein the 5 to 6 membered heterocycle does not contain an oxo or imino substitued ring atom; and
RXb, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy.
In a preferred embodiment of ring B, ring B is selected from the group consisting of a carbocyclic group of 5, 6, or 7 carbon atoms selected from -cyclopentylene-, -cyclohexylene-, -cycloheptylene-, -cyclopentenylene-, -cyclohexenylene-, and -phenylene-; a heterocycle of 5, 6, or 7 atoms selected from -pyrrolidinylene-, -piperidinylene-, -homopiperidinylene-, and -thiophenylene-; a bicyclic ring system selected from the group consisting of: 
a tricyclic ring system selected from the group consisting of: 
and a tetracyclic ring system selected from the group consisting of: 
and Ring B is substituted with 0, 1, 2, 3, or 4 R11 groups.
In another preferred embodiment of ring B, ring B is selected from the group consisting of -cyclopent-1,2-diyl-, -cyclopent-1,3-diyl-, -cyclohex-1,2-diyl-, -cyclohex-1,3-diyl-, -cyclohex-1,4-diyl-, -cyclohept-1,3-diyl-, -cyclopenten-3,5-diyl-, -phen-1,2-diyl-, -phen-1,3-diyl-, -phen-1,4-diyl-, -pyrrolidin-1,4-diyl-, -pyrrolidin-2,4-diyl-, -piperidin-1,4-diyl-, -piperidin-1,3-diyl-, -thiophen-2,3-diyl-, and 
a bicyclic ring system selected from the group consisting of: 
a tricyclic ring system selected from the group consisting of: 
and a tetracyclic ring system selected from the group consisting of: 
and Ring B is substituted with 0, 1, or 2 R11 groups.
In another preferred embodiment of ring B, ring B is selected from the group consisting of: 
and Ring B is substituted with 0-1 R11.
In another preferred embodiment of ring B, ring B is selected from the group consisting of: 
and Ring B is substituted with 0 -1 R11.
In another preferred embodiment of ring B, ring B is selected from the group consisting of: 
and Ring B is substituted with 0 -1 R11.
In another preferred embodiment of ring B, ring B is selected from the group consisting of: 
and Ring B is substituted with 0 -1 R11.
In another preferred embodiment of ring B, ring B is selected from the group consisting of: 
and Ring B is substituted with 0 -1 R11.
In another preferred embodiment of ring B, ring B is selected from the group consisting of: 
and Ring B is substituted with 0-1 R11.
In another preferred embodiment of ring B, ring B is: 
and Ring B is substituted with 0-1 R11.
In another preferred embodiment of ring B, ring B is selected from the group consisting of: 
and Ring B is substituted with 0-1 R11.
In a preferred embodiment of R3 and R3a, R3 is selected from C1-C4 alkyl, C2-C4 alkenyl, and C2-C4 alkynyl; and R3a is H.
In another preferred embodiment of R3 and R3a, R3 and R3a may be combined to form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl moiety.
In another preferred embodiment of R3 and R3a, R3 and R3a may be combined to form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl moiety.
In another preferred embodiment of R3, R3 may be selected from the corresponding substituents depicted in Group B of Table 1.
In a preferred embodiment of R5 and R5a, R5 is selected from C1-C4 alkyl, C2-C4 alkenyl, and C2-C4 alkynyl; and R5a is H.
In another preferred embodiment of R5 and R5a, R5 and R5a may be combined to form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl moiety.
In another preferred embodiment of R5, R5 may be selected from the corresponding substituents depicted in Group B of Table 1.
It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment to descibe additional even more preferred embodiments of the present invention.
In a second embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable carrier.
In a third embodiment, the present invention provides a method for the treatment of neurological disorders associated with P-amyloid production comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of Formula (I).
In a preferred embodiment the neurological disorder associated with xcex2-amyloid production is Alzheimer""s Disease.
In a fourth embodiment, the present invention provides a method for the treatment of neurological disorders associated with xcex2-amyloid production comprising administering to a host in need of such treatment a therapeutically effective amount of a metalloprotease inhibitor which inhibits xcex3 secretase activity.
In a preferred embodiment the neurological disorder associated with xcex2∇amyloid production is Alzheimer""s Disease.
In a preferred embodiment, the metalloprotease inhibitor is a hydroxamic acid.
In a more preferred embodiment, the metalloprotease inhibitor is a hydroxamic acid with an IC50 value of less than 10 xcexcM in the Axcex2 immunoprecipitation assay.
In a fifth embodiment, the present invention provides a method for inhibiting xcex3 secretase activity for the treatment of a physiological disorder associated with inhibiting xcex3 secretase activity comprising administering to a host in need of such inhibition a therapeutically effective amount of a compound of Formula (I) that inhibits xcex3 secretase activity.
In a preferred embodiment the physiological disorder associated with inhibiting xcex3 secretase activity is Alzheimer""s Disease.
In a sixth embodiment, the present invention provides a compound of Formula (I) for use in therapy.
In a preferred embodiment the present invention provides a compound of Formula (I) for use in therapy of Alzheimer""s Disease.
In a seventh embodiment, the present invention provides for the use of a compound of Formula (I) for the manufacture of a medicament for the treatment of Alzheimer""s Disease.
As used herein, the term xe2x80x9cAxcex2xe2x80x9d denotes the protein designated Axcex2, xcex2-amyloid peptide, and sometimes xcex2/A4, in the art. Axcex2 is an approximately 4.2 kilodalton (kD) protein of about 39 to 43 amino acids found in amyloid plaques, the walls of meningeal and parenchymal arterioles, small arteries, capillaries, and sometimes, venules. The isolation and sequence data for the first 28 amino acids are described in U.S. Pat. No 4,666,829. The 43 amino acid sequence is:
However, a skilled artisan knows that fragments generated by enzymatic degradation can result in loss of amino acids 1-10 and/or amino acids 39-43. Thus, an amino acid sequence 1-43 represents the maximum sequence of amino acids for Axcex2 peptide.
The term xe2x80x9cAPPxe2x80x9d, as used herein, refers to the protein known in the art as xcex2∇amyloid precursor protein. This protein is the precursor for Axcex2 and through the activity of xe2x80x9csecretasexe2x80x9d enzymes, as used herein, it is processed into Axcex2. Differing secretase enzymes, known in the art, have been designated xcex2 secretase, generating the N-terminus of Axcex2, a secretase cleaving around the 16/17 peptide bond in Axcex2, and xe2x80x9cxcex3 secretasesxe2x80x9d, as used herein, generating C-terminal Axcex2 fragments ending at position 38, 39, 40, 41, 42, and 43 or generating C-terminal extended precursors which are subsequently truncated to the above polypeptides.
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced.
When any variable (e.g., R5b) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R5b, then said group may optionally be substituted with up to two R5b groups and R5b at each occurrence is selected independently from the definition of R5b. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9calkylxe2x80x9d or xe2x80x9calkylenexe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; for example, xe2x80x9cC1-C6 alkylxe2x80x9d denotes alkyl having 1 to 6 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl. Preferred xe2x80x9calkylxe2x80x9d group, unless otherwise specified, is xe2x80x9cC1-C4 alkylxe2x80x9d.
As used herein, xe2x80x9calkenylxe2x80x9d or xe2x80x9calkenylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain. Examples of xe2x80x9cC2-C6 alkenylxe2x80x9d include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 2-pentenyl, 3-pentenyl, hexenyl, and the like.
As used herein, xe2x80x9calkynylxe2x80x9d or xe2x80x9calkynylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more carbon-carbon triple bonds which may occur in any stable point along the chain, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like.
xe2x80x9cAlkoxyxe2x80x9d or xe2x80x9calkyloxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy. Similarly, xe2x80x9calkylthioxe2x80x9d or xe2x80x9cthioalkoxyxe2x80x9d is represents an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo. Unless otherwise specified, preferred halo is fluoro and chloro. xe2x80x9cCounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, heptafluoropropyl, and heptachloropropyl. xe2x80x9cHaloalkoxyxe2x80x9d is intended to mean a haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge; for example trifluoromethoxy, pentafluoroethoxy, 2,2,2-trifluoroethoxy, and the like. xe2x80x9cHalothioalkoxyxe2x80x9d is intended to mean a haloalkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge. xe2x80x9cCycloalkylxe2x80x9d is intended to include saturated ring groups, having the specified number of carbon atoms. For example, xe2x80x9cC3-C6 cycloalkylxe2x80x9d denotes such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
As used herein, xe2x80x9ccarbocyclexe2x80x9d is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin). Preferred xe2x80x9ccarbocyclexe2x80x9d are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic ringxe2x80x9d is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3 or 4 heteroatoms, preferably 1, 2, or 3 heteroatoms, independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and 0 atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. Preferred 5 to 10 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl, and isoquinolinyl. Preferred 5 to 6 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl; more preferred 5 to 6 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, and tetrazolyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
As used herein, the term xe2x80x9carylxe2x80x9d, xe2x80x9cC6-C10 arylxe2x80x9d or aromatic residue, is intended to mean an aromatic moiety containing the specified number of carbon atoms; for example phenyl, pyridinyl or naphthyl. Unless otherwise specified, xe2x80x9carylxe2x80x9d may be unsubstituted or substituted with 0 to 3 groups selected from H, OH, OCH3, Cl, F, Br, I, CN, NO2, NH2, N(CH3)H, N(CH3)2, CF3, OCF3, C(xe2x95x90O)CH3, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, CH3, CH2CH3, CO2H, and CO2CH3.
The compounds herein described may have asymmetric centers. One enantiomer of a compound of Formula (I) may display superior biological activity over the opposite enantiomer. Both of the configurations are considered part of the invention. For example, the amino attachment to ring B may exist in either an S or R configuration. An example of such configuration includes, 
but is not intended to be limited to this example of ring B. When required, separation of the racemic material can be achieved by methods known in the art. Additionally, the connection point of xe2x80x94Wxe2x80x94Xxe2x80x94Yxe2x80x94Z or other substituents to ring B may exist in two enantiomers. Both enantiomers are considered part of this invention. Additionally, the carbon atoms to which R3 and R5 are attached may describe chiral carbons which may display superior biological activity over the opposite enantiomer. For example, where R3 and R5 are not H, then the configuration of the two centers may be described as (2R,3R), (2R,3S), (2S,3R), or (2S,3 S). All configurations are considered part of the invention; however, the (2R,3S) and the (2S,3R) are preferred and the (2R,3S) is more preferred.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharnaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference. xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I), and the like.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.
The novel compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
Methods for the synthesis of succinylamino lactams are known in the art and are disclosed in a number of references including PCT publication number WO 96/29313, which is hereby incorporated by reference.
Disubstituted succinate derivatives can be prepared by a number of known procedures. The procedure of Evans (D. A. Evans et al, Org. Synth. 86, p83 (1990)) is outlined in Scheme 1 where acylation of an oxazolidinone with an acylating agent such as an acid chloride provides structures 1. Alkylation to form 2 followed by cleavage of the chiral auxiliary and subsequent alkylation of the dianion of the carboxylic acid 3 provides a variety of disubstituted succinates which can be separated and incorporated into structures of Formula (I) by those skilled in the art. Additional examples are found in P. Becket, M. J. Crimmin, M. H. Davis, Z. Spavold, Synlett, (1993), 137-138, incorporated herein by reference. 
Diastereomerically pure succinate derivatives can be accessed using the chemistry outlined below, adapted from P. Becket, M. J. Crimmin, M. H. Davis, Z. Spavold, Synlett, (1993), 137-138 incorporated herein by reference. This reference provides the synthesis below to obtain compound 9. Compound 11 is used as an intermediate and is prepared from 9 by hydrogenation of the allyl group followed by coupling of 9-fluorenemethanol under standard conditions using DCC and DMAP in CH2Cl2. Deprotection of the tert-butyl ester is accomplished by treatment with 50% trifluoroacetic acid.
Additional methods useful for the preparation of succinate derivatives are known by those skilled in the art. Such references include, McClure and Axt, Bioorganic and Medicinal Chemistry Letters, 8 (1998) 143-146; Jacobson and Reddy, Tetrahedron Letters, Vol 37, No. 46, 8263-8266 (1996); Pratt et al., SYNLETT, May 1998, p. 531; WO 97/18207; and WO 98/51665. The synthetic disclosures of W097/18207 and WO 98/51665 are hereby incorporated by reference.
Additional methods useful for the preparation of succinate derivatives are disclosed in WO00/07995 and WO 00/38618, which are hereby incorporated in their entirety by reference. 
A variety of compounds of Formula (I) can be prepared by methods described in Scheme 4. The protected xcex1 amine 3 of the a amino-e caprolactam can be prepared by methods well known in the literature for amino protecting groups as discussed in Theodora W. Greene""s book xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, like N-Boc using di-t-butyldicarbonate in an appropriate solvent like DMSO. A sulfur atom can be introduced into the ring providing L-xcex1 amino-xcex2 thio-xcex5 caprolactam according to the procedure in S. A. Ahmed et al, FEBS Letters, (1984), vol. 174, pages 76-9 (Scheme 3).
One skilled in the art can extend this methodology to the synthesis of xcex2 amino and oxygen containing rings by analogy. The sulfur-containing molecules can also be oxidized to the sulfoxide and sulfone by methods known to one skilled in the art. 
The lactam nitrogen of compound 13 can be alkylated by generating the anion with bases such as LDA, lithium bis(trimethylsilyl)amide or sodium hydride in solvents like THF, with or without cosolvents such as DMPU or HMPA and reacting this with a variety of groups containing leaving groups (Xxe2x80x3) like bromide, iodide, mesylate or tosylate. Alkylating agents such as a bromo amides, ketones and acids can be prepared by a number of literature methods including halogenation of amino acids by diazotization or are commercially available. Other suitable alkylating agents such as alkyl, allylic and benzylic halides can be formed form a variety of precursors such as free-radical addition of halides or activation of alcohols, and other chemistries known to those skilled in the art. For discussion of these types of reactions, see Carey, F. A. and Sundberg, R. J., Advanced Organic Chemistry, Part A, New York: Plenum Press, 1990, pages 304-305, 342-347, 695-698.
The N-Boc protecting group can be removed by any number of methods well known in the literature like TFA in methylene chloride to give the compound 15. The amine 15 can be coupled to an appropriately substituted carboxylic acid or acid chloride by methods well described in the literature for making amide bonds, like TBTU in DMF with a base like NMM to give the elaborated compound 16. Compounds 16 can be alkylated using standard bases like LDA, NaH, or NaHMDS to deprotonate the amide followed by addition of an alkylating agent with an appropriate leaving group like halide, mesylate, or triflate in an appropriate solvent to provide compounds 17 with an R6 substituent. The t-butyl ester is then removed by treatment with TFA in methylene chloride to give the carboxylic acid 17.
It is understood that methods useful for the preparation of Wxe2x80x94Xxe2x80x94Yxe2x80x94Z derivatives, on a non-commercial scale, are known by those skilled in the art or readily ascertainable from the literature. Such methods useful for the preparation of Wxe2x80x94Xxe2x80x94Yxe2x80x94Z derivatives are disclosed in WO00/07995 and WO 00/38618, which are hereby incorporated in their entirety by reference. 
The final compounds 18 were prepared by treating the activated carboxylic acid of 17 with an appropriately substituted amine. For instance, activation of the carboxylic acid with HATU (Oxe2x80x94(7-azabenzotriazol-1-yl)-1,1,3,3,-tetramethyluronium hexafluorophosphate) or PyBOP (benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate) or other coupling agents known to those skilled in the art allows condensation with ammonia to form primary amides. Similarly, condensation of the activated acid with hydroxylamine hydrochloride provides the hydroxamic acid, or reaction with a primary or secondary amine provides the substituted amine derivative. Activation of the acid with PyBrOP (bromo-tris-pyrrolidino-phosphonium hexafluorophosphate) followed by addition of an alcohol and 4-dimethylaminopyridine allows formation of the ester directly. For additional acylation reactions see for example Carey, F. A. and Sundberg, R. J., Advanced Organic Chemistry, Part A, New York: Plenum Press, 1990, pages 475-479.
Additional Examples of compounds of Formula (I) can be prepared as shown in Scheme 5. A suitable resin for solid phase synthesis such as Fmoc (Fluorenylmethylcarbonyl)-protected hydroxylamine bound to polystyrene beads can be purchased from Novabiochem, Inc. Deprotection of the Fmoc group under standard conditions using 20% piperidine in DMF provides trityl-linked hydroxylamine resin. Coupling of a fluorenylmethyl-protected succinic acid derivative such as 20 with a coupling agent such as HATU in a suitable solvent like DMF or N-methylpyrrolidinone provides the support-bound hydroxamate 21. The Fluorenylmethyl ester can be removed using 20% piperidine in DMF to provide the free carboxylic acid which can be coupled to amines like the caprolactam 22 (which is available using chemistry outlined in Scheme 4) using PyBOP (benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate) and a suitable base like DIEA in DMF or NMP. The support-bound intermediate 23 can then be elaborated to biaryl structures of the type 24 using typical Suzuki coupling conditions employing a catalyst such as Palladium complexes like tetrakis(triphenylphosphine)-palladium with 2M aqueous sodium carbonate as a base in a suitable solvent like THF or DME and an excess of a boronic acid. The final compounds are liberated from the support employing dilute (5%) trifluoroacetic acid in CH2Cl2 and purified by conventional chromatography. 
General Procedure for Solid-phase Synthesis According to Scheme 5.
Resin 20 of Scheme 5:
Fmoc-protected resin 19 (2.0 g, 0.78 mmol/g, 1.56 mmol) is purchased from Novabiochem and swelled in 20 ml of CH2Cl2 for 1 hour. The CH2Cl2 is removed and the resin is then treated with 25% v/v piperidine in DMF (8 mL) and allowed to shake slowly for 16 h. The solvent was removed by filtration and the resin was shaken with an additional 8 mL of 25% v/v piperidine in DMF for 2 h at room temperature. The solvents were removed by filtration, and the resin 20 was rinsed 3xc3x97 with 20 mL of DMF, 3xc3x97 with 20 mL of methanol, and 3xc3x97 with 20 mL of CH2Cl2 and dried in vacuo.
Succinate 10 of Scheme 2:
Succinate 9 is prepared according to the literature procedure (P. Becket, M. J. Crimmin, M. H. Davis, Z. Spavold, Synlett, (1993), 137-138; WO 97/18207; WO 98/51665). Succinate 9 (17.8 g, 66 mmol) is dissolved in 250 mL of ethyl acetate and placed in a Parr shaker bottle. To the solution is added 890 mg of 5% palladium on carbon, and the bottle is pressurized to 40 psi with hydrogen gas and shaken for 2.5 h at room temperature. The hydrogen is removed and the palladium catalyst is removed by filtration through a pad of celite. Concentration of the ethyl acetate solution provides 17.5 g (98%) of succinate 10. No further purification is necessary. MS (Mxe2x88x92H)+=271.
Succinate 21 of Scheme 5:
Succinate 10 (6.3 g, 23.1 mmol) is dissolved in 125 mL of CH2Cl2 and 4.8 g (23.3 mmol) of dicyclohexylcarbodiimide is added. The solution is stirred at room temperature for 30 min and then 4.6 g (23.4 mmol) of 9-fluorenemethanol is added followed by 122 mg (1 mmol) of 4-dimethylaminopyridine. After 5 h of stirring at room temperature, the reaction solution was diluted with an additional 100 mL of CH2Cl2 and filtered through a pad of celite to remove precipitated dicyclohexylurea. The solution was then washed 3xc3x97 with 50 mL of a 1N HCl solution, 3 xc3x97 with 50 mL of a saturated sodium bicarbonate solution, and 2xc3x97 with 50 mL of brine. The crude product was dried over MgSO4 and soncentrated onto 15 g of silica gel. Chromatography eluting with a gradient of 2.5% to 5% ethyl acetate/hexanes provided 6.4 g (61%) of the diester as an oil. The purified diester (6.4 g 14.2 mmol) is then dissolved in 25 mL of CH2Cl2, 25 mL of trifluoroacetic acid is added, and the reaction solution is stirred at room temperature for 2 h. The reaction solution is directly concentrated in vacuo to an oil which is then redissolved in 25 mL of toluene and reconcentrated, followed by drying in vacuo to provide 6.3 g (98%) of the desired succinate 9 as an oil which solidifies on standing. MS (M+Na)+=471, (M+2Na)+=439.
Caprolactam 23 of Scheme 5:
Boc-caprolactam 14 (5.0 g, 21.9 mmol) is dissolved in 60 mL of THF and chilled to -78xc2x0 C. To the chilled solution is added 24 mL of a 1.0 M solution of lithium bis(trimethylsilyl)amide in THF, and the solution was brounght to 0xc2x0 C. and stirred for 15 min. To the anion solution was added 6.5 g (22 mmol) of 3-iodobenzyl bromide (Aldrich) and the the solution was allowed to warm to room temperature and stirred for 18 h. The reaction solution was diluted with 50 mL of water and extracted 3xc3x97 with ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude product was purified by chromatography eluting with a gradient of 5-20% ethyl acetate/hexanes to afford 7.0 g (72%) of the title compound as a white solid. MS (M+Na)+=467.
Resin 22 of Scheme 5:
Resin 22 (2.0 g, 0.78 mmol/g, 1.56 mmol) was swollen in 3 mL of DMF. In a separate flask, 1.85 g (4.68 mmol) of succinate 21 was dissolved in 3 mL of DMF and 2.5 mL of N,N-diisopropylethylamine (14 mmol) wsa added, followed by 1.81 g (4.68 mmol) of HATU. The solution containing the active ester was added to the slurried resin and the reaction suspension was slowly shaken for 18 h. The resin was then washed 3xc3x97 with 20 mL of DMF, 3xc3x97 with 20 mL of methanol, and 3xc3x97 with 20 mL of CH2Cl2. Loading of the resin was determined by Fmoc quantitation to be 0.25 mmol/g, see Reddy, M. P.; Voelker, P.J. Int. J. Pept. Protein Res. 1998, 31, 345-348.
Resin 24 of Scheme 5:
Resin 22 (2.0 g, 0.25 mmol/g, 0.5 mmol) was suspended in 10 mL of 25% piperidine in DMF. The suspended resin was shaken for 30 min at room temperature, and then the resin was washed 3xc3x97 with 20 mL of DMF, 3xc3x97 with 20 mL of methanol, and 3xc3x97 with 20 mL of CH2Cl2. Deprotected resin (1.0 g, 0.25 mmol) was swollen in 2 mL of DMF. To the slurry was added 650 mg (1.25 mmol) of PyBOP and 217 mL (1.25 mmol) of DIEA. Separately, 443 mg (0.97 mmol) of caprolactam 23 was dissolved in 2 mL of DMF and 436 mL (2.5 mmol) of DIEA was added. The caprolactam solution was added to the resin slurry and the resin was mixed for 18 h at room temperature. The solvents were then removed and the coupling was repeated, with shaking at room temperature for 6 h. The resin was then washed 3xc3x97 with 10 mL of DMF, 3xc3x97 with 10 mL of methanol, and 3xc3x97 with 10 mL of CH2Cl2.
Products 25 of Scheme 5:
A 70 mg (17.5 mmol) portion of resin 24 was suspended in 1 mL of THF in a screw-cap vial. To the slurry was added a boronic acid (0.15 mmol), 150 mL of a 2 M solution of sodium carbonate, and 15 mg (13 mmol) of tetrakis(triphenylphosphine)palladium. The vial was tightly closed and heated to 60xc2x0 C. for 16 h using a dry heater on a shaker table. The solvents were then removed by filtration and the resin was washed 3xc3x97 with THF (2 mL), 3xc3x97 with methanol (2 mL), 3xc3x97 with water, and 3xc3x97 with CH2Cl2. The resins were then placed in a glass vial and cleaved with 1 mL of 5% trifluoroacetic acid in CH2Cl2 for 30 min. The solution ws filtered off and the resin was washed with an additional 2 mL of CH2Cl2 and the combined filtrates were evaporated to dryness to yield the crude products 25. The products were purified by chromatography eluting with 10-100% ethyl acetate in hexanes to yield 13.0 to 6.0 mg (14-60%) of the final products.
Additional Examples of compounds of Formula (I) can be prepared as shown in Scheme 6. A suitable resin for solid phase synthesis such as Fmoc (Fluorenylmethylcarbonyl)-protected peptide amide linker (PAL)-derivatized polystyrene beads can be purchased from Perkin Elmer Biosystems, Inc. Deprotection of the Fmoc group under standard conditions using 20% piperidine in DMF provides the free benzylamine. Coupling of a succinic acid derivative such as 28 (which is available using chemistry outlined in Scheme 4) with a coupling agent such as HATU in a suitable solvent like DMF or N-methylpyrrolidinone provides the support-bound amide 29. The support-bound intermediate 29 can then be elaborated to biaryl structures of the type 24 using typical Suzuki coupling conditions employing a catalyst such as Palladium complexes like tetrakis(triphenylphosphine)-palladium with 2M aqueous sodium carbonate as a base in a suitable solvent like THF or DME and an excess of a boronic acid. The final compounds are liberated from the support employing 50% trifluoroacetic acid in CH2Cl2 and can be purified by conventional chromatography or preparative HPLC. 
General Procedure for Solid-phase Synthesis According to Scheme 6
Resin 27 of Scheme 6:
Fmoc-protected PAL resin 26 (0.80 g, 0.50 mmol/g, 0.40 mmol) is purchased from Advanced Chemtech and swelled in 20 ml of CH2Cl2 for 1 hour. The CH2Cl2 is removed and the resin is then treated with 25% v/v piperidine in DMF (6 mL) and allowed to shake slowly for 1 h. The solvents were removed by filtration, and the resin 27 was rinsed 3xc3x97 with 20 mL of DMF, 3xc3x97 with 20 mL of methanol, and 3xc3x97 with 20 mL of CH2Cl2. and dried in vacuo.
Acid 28 of Scheme 6:
To a solution of 0.100 g (367 mmol) of succinate 10 dissolved in 2.0 mL of dry DMF was added 0.120 mL (1.10 mmol) of N-methylmorpholine. A second solution containing 0.139 g (0.403 mmol) of caprolactam 23 of Scheme 5 dissolved in 2.0 mL of DMF was then added. To the mixed solution was added 229 mg (0.440 mmol) of PyBop and the reaction solution was stirred for 16 h at room temperature. The reaction solution was diluted with water (20 mL) and extracted 3 xc3x97 with 100 mL of ethyl acetate. The combined organic layers were dried with Na2SO4 and concentrated under reduced pressure. The resulting oil was purified by chromatography eluting with a gradient of 5-20% ethyl acetate in hexanes to provide 0.195 g (0.360 mmol, 98%) of the tert-butyl ester of Acid 28 (MS M+Na=621). The purified ester (0.195 g, 0.360 mmol) was dissolved in 10 mL of 25% trifluoroacetic acid in CH2Cl2 and stirred for 2 h at room temperature. The solvents were removed under reduced pressure and the acid was redissolved in 5 mL of toluene and reconcentrated 2xc3x97 to remove residual TFA. The crude acid was found to be pure by 1H NMR and was used in Scheme 6 without further purification.
Resin 29 of Scheme 6:
Resin 27 (800 mg, 0.40 mmol) was solvated in 4.0 mL of dry DMF and and 0.63 mL (3.6 mmol) of diisopropylethylamine was addedfollowed by a solution of Acid 28 dissolved in 4 mL of DMF. To the slurry was then added 0.465 g (1.2 mmol) of HATU and the slurry was shaken for 26 h at room temperature. The solvents were removed by filtration, and the resin 29 was rinsed 3xc3x97 with 20 mL of DMF, 3xc3x97 with 20 mL of methanol, and 3xc3x97 with 20 mL of CH2Cl2. and dried in vacuo.
Products 30 of Scheme 6:
A 75 mg (0.38 mmol/g, 28.8 mmol) portion of resin 24 was suspended in 1 mL of THF in a screw-cap vial. To the slurry was added a boronic acid (0.33 mmol), 150 mL of a 2 M solution of sodium carbonate, and 15 mg (13 mmol) of tetrakis(triphenylphosphine)palladium. The vial was tightly closed and heated to 60xc2x0 C. for 16 h using a dry heater on a shaker table. The solvents were then removed by filtration and the resin was washed 3xc3x97 with THF (2 mL), 3xc3x97 with methanol (2 mL), 3 x with water, and 3xc3x97 with CH2Cl2. The resins were then placed in a glass vial and cleaved with 1 mL of 5% trifluoroacetic acid in CH2Cl2 for 2 h. The solution was filtered off and the resin was washed with an additional 2 mL of CH2Cl2 and the combined filtrates were evaporated to dryness to yield the crude products 25. The products were purified by chromatography eluting with 10-100% ethyl acetate in hexanes to yield 0.5 to 2.0 mg (14-60%) of the final products.
The internal phenyl ring can be exchanged for a pyridine ring using chemistry outlined in Scheme 7. The chloromethyl pyidine 33 is prepared using a known procedure reported in Nutaitis, Charles F.; Ledeboer, Mark W. Org. Prep. Proced. Int. (1992), 24(2), 143-6 Incorporated herein by reference. After freebasing the pyridine, alkylation with the Boc-caprolactam provides pyridine intermediate 34, which can be elaborated to the protected amide 35 with succinate 10. Substitution can then be introduced using Suzuki methodology employing a palladium source such as tetrakis(triphenylphosphine) palladium(0) or bis(diphenylphosphinoferrocene) palladium(II) dichloride and a suitable base such as sodium carbonate or triethylamine in a solvent such as THF or toluene containing 10% methanol. Stille chemistry is also possible using a suitable palladium source such as tetrakis(triphenylphosphine)palladium(0) and an aryl or vinyl tin derivative in a solvent such as benzene, toluene, or xylenes. The tert-butyl ester is then deprotected under standard acidic conditions using trifluoroacetic acid and the amide is formed under standard conditions to provide products 36. 
General Procedure for Synthesis According to Scheme 7
The chloromethyl pyidine HCl salt 33 is prepared using a known procedure reported in Nutaitis, Charles F.; Ledeboer, Mark W. Org. Prep. Proced. Int. (1992), 24(2), 143-6.
Caprolactam 34:
Pyridine HCl salt 33 (2.0 g, 8.3 mmol) is dissolved in 50 mL of a saturated NaHCO3 solution and the solution is extracted with 30 mL of CH2Cl2 3xc3x97 followed by concentration of the organic layers to provide the free base. Separately, 1.8 g (7.8 mmol) of caprolactam 13 is dissolved in 40 mL of dry THF and chilled to xe2x88x9278xc2x0 C. To the solution was added 8.7 mL of a 1M solution of sodium bis(trimethylsilyl) amide. The solution was brought to 0xc2x0 C. and stirred for 30 min. To the resultant anion was added a solution of 1.7 g (8.3 mmol) of pyridine 33 free base dissolved in 40 mL of THF. The resulting reaction solution was stirred at room temperature for 18 h and then heated to 50xc2x0 C. and stirred an additional 3 h. The reaction solution was allowed to cool and then 50 mL of water was added and the aqueous layer was extracted 2xc3x97 with 100 mL of ethyl acteate. The combined organic layers were dried and concentrated under reduced pressure to provide the crude product which was purified by chromatography eluting with 20 to 100% ethyl acetate in hexanes to provide 1.5 g (51%) of caprolactam 34 as an oil.
Amide 35:
Caprolactam 34 (0.40 g, 1.0 mmol) is dissolved in 20 mL of 50% trifluoroacetic acid in CH2Cl2 and stirred at room temperature for 30 min. The solvents were then removed under reduced pressure and the resulting oil was redissolved in 5 mL of toluene and reconcentrated to remove residual TFA. Separately, 0.270 g (1.0 mmol) of succinate 10 was dissolved in 5.0 mL of dry DMF and 0.44 mL (4 mmol) of N-methylmorpholine was added followed by 0.50 g (1.3 mmol) of HATU and the resulting solution was stirred at room temperature for 30 min. The crude deprotected caprolactam from above was dissolved in 5.0 mL of dry DMF and added to the succinate solution and the resulting solution was heated to 50xc2x0 C. and stirred for 2 days. The solution was then diluted with 20 mL of water and extracted with 3 50 mL portions of ethyl acetate. The combined organic layers were dried and concentrated under reduced pressure to provide an oil which was purified by chromatography eluting with 20 to 50% ethyl acetate in hexanes to provide 0.40 g (70%) of the Amide 35.
Additional examples can be prepared by the method shown in Scheme 8. Coupling of an amine onto a commercially available aldehyde-derived resin 37 under conditions for reductive amination such as sodium tris(acetoxy)borohydride in CH2Cl2 containing 1% acetic provides a support-bound amine 38. The carboxylic acid 39 can then be coupled to the support-bound amine generating an amide 40 which can be liberated from the support employing trifluoroacetic acid in CH2Cl2. 
General Procedure for Solid-phase Synthesis According to Scheme 8
Resin 38 of Scheme 5:
Aldehyde-derived resin 37 (200 mg, 0.5 mmol/g, 0.1 mmol) is purchased from Perkin Elmer Biosystems and swelled in 3 ml of CH2Cl2 for 1 hour. An amine (1.0 mmol), sodium tris(acetoxy)borohydride (106 mg, 0.5 mmol) and acetic acid (30 uL, 1%) are added and the reaction is shaken on a shaker table for 16 h at room temperature. The solvents were removed by filtration and the resin 38 was rinsed 3xc3x97 with 20 mL of DMF, 3xc3x97 with 20 mL of methanol, and 3xc3x97 with 20 mL of CH2Cl2. and dried in vacuo.
Products 40 of Scheme 8:
Carboxylic acid 39 (23 mg, 0.045 mmol), diisopropylethylamine (13 mL, 0.075 mmol) and HATU (17.1 mg, 0.045 mmol) were mixed in 0.5 mL of DMF for 30 min. Amine-derived resins 38 (30 mg, 0.015 mmol) were then added and the suspension was shaken at room temperature for 16 h. . The solvents were removed by filtration and the resins were rinsed 3xc3x97 with 20 mL of DMF, 3xc3x97 with 20 mL of methanol, and 3xc3x97 with 20 mL of CH2Cl2. The isolated resins were then cleaved by the addition of 0.50 mL of trifluoroacetic acid. The product solutions were concentrated and redissolved in 0.5 mL of methanol and reconcentrated 2xc3x97 to remove residual TFA. Product yields ranged from 0-100% based on the structure of the amine.
The compounds of Formula (I) of the present invention can also be prepared from aminolactam 42 and succinic acid derivatives 41 using amide bond syntheses known in the art, including methods commonly used in peptide syntheses, such as HATU, TBTU, BOP, pyBOP, EDC, CDI, DCC, hydroxysuccinimide, mixed carboxylic anhydride, and phenyl ester mediated couplings, as illustrated in Scheme 9 for the synthesis of aminolactam 43, an embodiment of the present invention. 
Depending on the structure of the final product, it is appreciated by those skilled in the art that protecting groups or precursor functionality convertable to the desired groups may be desireable. Protecting groups and their use in synthesis are described in Green and Wuts, Protective Groups in Organic Synthesis, (Wiley 1991). The use of protecting groups is further illustrated in Scheme 10, in which the succinate half-ester 44 (Becket et al., Synlett 1993, 137-138) is coupled to the aminobenzodiazepine 45 (Sherrill and Sugg, J. Org. Chem. 1995, 60, 730-734; Bock et al., J. Med. Chem., 1993, 36, 4276-4292) to give ester 46, followed by conversion of the ester group to the primary amide 47. 
Methods for the synthesis of lactams as contemplated by the present invention in lactam ring B in Formula (I), including amino benzodiazepines, are known in the art and are disclosed in a number of references including PCT publication number WO 98/28268, which is hereby incorporated by reference. Additional references include Bock, et al, J. Org. Chem., 1987, 52, 3232-3239 and Sherrill et al, J. Org. Chem., 1995, 60, 730-734; Walsh, D. A., Synthesis, September 1980, p.677.
The carbocyclic and heterocyclic B groups can be synthesized using methods described in WO 98/28268, W099/32453, and WO/99/67221 and references cited therein. The synthetic disclosures of WO 98/28268, W099/32453, and WO/99/67221, and the references which are cited within these references, are hereby incorporated by reference.